InVivoMAb anti-mouse CTLA-4 (CD152)

Catalog #BE0164
Product Citations:
152
Clone:
9D9
Reactivities:
Mouse

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Product Details

The 9D9 monoclonal antibody reacts with mouse CTLA-4 (cytotoxic T lymphocyte antigen-4) also known as CD152. CTLA-4 is a 33 kDa cell surface receptor encoded by the Ctla4 gene that belongs to the CD28 family of the Ig superfamily. CTLA-4 is expressed on activated T and B lymphocytes. CTLA-4 is structurally similar to the T-cell co-stimulatory protein, CD28, and both molecules bind to the B7 family members B7-1 (CD80) and B7-2 (CD86). Upon ligand binding, CTLA-4 negatively regulates cell-mediated immune responses. CTLA-4 plays roles in induction and/or maintenance of immunological tolerance, thymocyte development, and regulation of protective immunity. The critical role of CTLA-4 in immune down-regulation has been demonstrated in CTLA-4 deficient mice, which succumb at 3-5 weeks of age due to the development of a lymphoproliferative disease. CTLA-4 is among a group of inhibitory receptors being explored as cancer treatment targets through immune checkpoint blockade. This CTLA-4 antibody has been extensively used in blocking/neutralization experiments and findings from a range of tumor models have established that the in vivo treatment of 9D9 monoclonal antibody results in intra-tumoral regulatory T cell depletion.

Specifications

Isotype Mouse IgG2b
Recommended Isotype Control(s) InVivoMAb mouse IgG2b isotype control, unknown specificity
Recommended Dilution Buffer InVivoPure pH 7.0 Dilution Buffer
Conjugation This product is unconjugated. Conjugation is available via our Antibody Conjugation Services.
Immunogen Not available or unknown
Reported Applications in vivo CTLA-4 neutralization
Western blot
in vivo intra-tumoral regulatory T cell depletion
Formulation PBS, pH 7.0
Contains no stabilizers or preservatives
Endotoxin <2EU/mg (<0.002EU/μg)
Determined by LAL gel clotting assay
Purity >95%
Determined by SDS-PAGE
Sterility 0.2 µm filtration
Production Purified from cell culture supernatant in an animal-free facility
Purification Protein A
RRID AB_10949609
Molecular Weight 150 kDa
Storage The antibody solution should be stored at the stock concentration at 4°C. Do not freeze.
in vivo CTLA-4 neutralization
Dai, M., et al. (2015). "Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies" Clin Cancer Res 21(5): 1127-1138. PubMed

PURPOSE: Immunomodulatory mAbs can treat cancer, but cures are rare except for small tumors. Our objective was to explore whether the therapeutic window increases by combining mAbs with different modes of action and injecting them into tumors. EXPERIMENTAL DESIGN: Combinations of mAbs to CD137/PD-1/CTLA-4 or CD137/PD-1/CTLA-4/CD19 were administrated intratumorally to mice with syngeneic tumors (B16 and SW1 melanoma, TC1 lung carcinoma), including tumors with a mean surface of approximately 80 mm(2). Survival and tumor growth were assessed. Immunologic responses were evaluated using flow cytometry and qRT-PCR. RESULTS: More than 50% of tumor-bearing mice had complete regression and long-term survival after tumor injection with mAbs recognizing CD137/PD-1/CTLA-4/CD19 with similar responses in three models. Intratumoral injection was more efficacious than intraperitoneal injection in causing rejection also of untreated tumors in the same mice. The three-mAb combination could also induce regression, but was less efficacious. There were few side effects, and therapy-resistant tumors were not observed. Transplanted tumor cells rapidly caused a Th2 response with increased CD19 cells. Successful therapy shifted this response to the Th1 phenotype with decreased CD19 cells and increased numbers of long-term memory CD8 effector cells and T cells making IFNgamma and TNFalpha. CONCLUSIONS: Intratumoral injection of mAbs recognizing CD137/PD-1/CTLA-4/CD19 can eradicate established tumors and reverse a Th2 response with tumor-associated CD19 cells to Th1 immunity, whereas a combination lacking anti-CD19 is less effective. There are several human cancers for which a similar approach may provide clinical benefit.

in vivo CTLA-4 neutralization
Zippelius, A., et al. (2015). "Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment" Cancer Immunol Res 3(3): 236-244. PubMed

CD40 stimulation on antigen-presenting cells (APC) allows direct activation of CD8(+) cytotoxic T cells, independent of CD4(+) T-cell help. Agonistic anti-CD40 antibodies have been demonstrated to induce beneficial antitumor T-cell responses in mouse models of cancer and early clinical trials. We report here that anti-CD40 treatment induces programmed death ligand-1 (PD-L1) upregulation on tumor-infiltrating monocytes and macrophages, which was strictly dependent on T cells and IFNgamma. PD-L1 expression could be counteracted by coadministration of antibodies blocking the PD-1 (programmed death-1)/PD-L1 axis as shown for T cells from tumor models and human donors. The combined treatment was highly synergistic and induced complete tumor rejection in about 50% of mice bearing MC-38 colon and EMT-6 breast tumors. Mechanistically, this was reflected by a strong increase of IFNgamma and granzyme-B production in intratumoral CD8(+) T cells. Concomitant CTLA-4 blockade further improved rejection of established tumors in mice. This study uncovers a novel mechanism of acquired resistance upon agonistic CD40 stimulation and proposes that the concomitant blockade of the PD-1/PD-L1 axis is a viable therapeutic strategy to optimize clinical outcomes.

in vivo CTLA-4 neutralization
Redmond, W. L., et al. (2014). "Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity" Cancer Immunol Res 2(2): 142-153. PubMed

Ligation of the TNF receptor family costimulatory molecule OX40 (CD134) with an agonist anti-OX40 monoclonal antibody (mAb) enhances antitumor immunity by augmenting T-cell differentiation as well as turning off the suppressive activity of the FoxP3(+)CD4(+) regulatory T cells (Treg). In addition, antibody-mediated blockade of the checkpoint inhibitor CTLA-4 releases the “brakes” on T cells to augment tumor immunotherapy. However, monotherapy with these agents has limited therapeutic benefit particularly against poorly immunogenic murine tumors. Therefore, we examined whether the administration of agonist anti-OX40 therapy in the presence of CTLA-4 blockade would enhance tumor immunotherapy. Combined anti-OX40/anti-CTLA-4 immunotherapy significantly enhanced tumor regression and the survival of tumor-bearing hosts in a CD4 and CD8 T cell-dependent manner. Mechanistic studies revealed that the combination immunotherapy directed the expansion of effector T-bet(high)/Eomes(high) granzyme B(+) CD8 T cells. Dual immunotherapy also induced distinct populations of Th1 [interleukin (IL)-2, IFN-gamma], and, surprisingly, Th2 (IL-4, IL-5, and IL-13) CD4 T cells exhibiting increased T-bet and Gata-3 expression. Furthermore, IL-4 blockade inhibited the Th2 response, while maintaining the Th1 CD4 and effector CD8 T cells that enhanced tumor-free survival. These data demonstrate that refining the global T-cell response during combination immunotherapy can further enhance the therapeutic efficacy of these agents.

in vivo CTLA-4 neutralization
Condamine, T., et al. (2014). "ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis" J Clin Invest 124(6): 2626-2639. PubMed

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.

in vivo CTLA-4 neutralization
Muller, P., et al. (2014). "Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells" Cancer Immunol Res 2(8): 741-755. PubMed

Antibody-drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30(+) malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies.

in vivo CTLA-4 neutralization
Bulliard, Y., et al. (2013). "Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies" J Exp Med 210(9): 1685-1693. PubMed

Fc gamma receptor (FcgammaR) coengagement can facilitate antibody-mediated receptor activation in target cells. In particular, agonistic antibodies that target tumor necrosis factor receptor (TNFR) family members have shown dependence on expression of the inhibitory FcgammaR, FcgammaRIIB. It remains unclear if engagement of FcgammaRIIB also extends to the activities of antibodies targeting immunoregulatory TNFRs expressed by T cells. We have explored the requirement for activating and inhibitory FcgammaRs for the antitumor effects of antibodies targeting the TNFR glucocorticoid-induced TNFR-related protein (GITR; TNFRSF18; CD357) expressed on activated and regulatory T cells (T reg cells). We found that although FcgammaRIIB was dispensable for the in vivo efficacy of anti-GITR antibodies, in contrast, activating FcgammaRs were essential. Surprisingly, the dependence on activating FcgammaRs extended to an antibody targeting the non-TNFR receptor CTLA-4 (CD152) that acts as a negative regulator of T cell immunity. We define a common mechanism that correlated with tumor efficacy, whereby antibodies that coengaged activating FcgammaRs expressed by tumor-associated leukocytes facilitated the selective elimination of intratumoral T cell populations, particularly T reg cells. These findings may have broad implications for antibody engineering efforts aimed at enhancing the therapeutic activity of immunomodulatory antibodies.

in vivo CTLA-4 neutralization
Wei, H., et al. (2013). "Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin" PLoS One 8(12): e84927. PubMed

90 days (and was probably curative) by a mechanism which included a systemic CD8(+) T cell response with tumor specificity and immunological memory. Strikingly, combined treatment of cisplatin and CD137/PD-1 mAb also gave rise to the long-term survival of mice with established TC1 lung tumors. A similar combination of the 2 mAbs and cisplatin should be considered for clinical ‘translation’.”}” data-sheets-userformat=”{“2″:14851,”3”:{“1″:0},”4”:{“1″:2,”2″:16777215},”12″:0,”14”:{“1″:2,”2″:1521491},”15″:”Roboto, sans-serif”,”16″:12}”>There is an urgent need for improved therapy for advanced ovarian carcinoma, which may be met by administering immune-modulatory monoclonal antibodies (mAbs) to generate a tumor-destructive immune response. Using the ID8 mouse ovarian cancer model, we investigated the therapeutic efficacy of various mAb combinations in mice with intraperitoneal (i.p.) tumor established by transplanting 3 x 10(6) ID8 cells 10 days previously. While most of the tested mAbs were ineffective when given individually or together, the data confirm our previous finding that 2 i.p. injections of a combination of anti-CD137 with anti-PD-1 mAbs doubles overall survival. Mice treated with this mAb combination have a significantly increased frequency and total number of CD8(+) T cells both in the peritoneal lavage and spleens, and these cells are functional as demonstrated by antigen-specific cytolytic activity and IFN-gamma production. While administration of anti-CD137 mAb as a single agent similarly increases CD8(+) T cells, these have no functional activity, which may be attributed to up-regulation of co-inhibitory PD-1 and TIM-3 molecules induced by CD137. Addition of the anti-cancer drug cisplatin to the 2 mAb combination increased overall survival >90 days (and was probably curative) by a mechanism which included a systemic CD8(+) T cell response with tumor specificity and immunological memory. Strikingly, combined treatment of cisplatin and CD137/PD-1 mAb also gave rise to the long-term survival of mice with established TC1 lung tumors. A similar combination of the 2 mAbs and cisplatin should be considered for clinical ‘translation’.

in vivo CTLA-4 neutralization
Dai, M., et al. (2013). "Long-lasting complete regression of established mouse tumors by counteracting Th2 inflammation" J Immunother 36(4): 248-257. PubMed

40% of mice with SW1 tumors remained healthy >150 days after last treatment and are probably cured. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity, required CD4 cells and involved CD8 cells and NK cells to a less extent. The 3 mAb combination significantly decreased CD19 cells at tumor sites, increased IFN-gamma and TNF-alpha producing CD4 and CD8 T cells and mature CD86 dendritic cells (DC), and it increased the ratios of effector CD4 and CD8 T cells to CD4Foxp3 regulatory T (Treg) cells and to CD11bGr-1 myeloid suppressor cells (MDSC). This is consistent with shifting the tumor microenvironment from an immunosuppressive Th2 to an immunostimulatory Th1 type and is further supported by PCR data. Adding an anti-CD19 mAb to the 3 mAb combination in the SW1 model further increased therapeutic efficacy. Data from ongoing experiments show that intratumoral injection of a combination of mAbs to CD137PD-1CTLA4CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity.”}” data-sheets-userformat=”{“2″:14851,”3”:{“1″:0},”4”:{“1″:2,”2″:16777215},”12″:0,”14”:{“1″:2,”2″:1521491},”15″:”Roboto, sans-serif”,”16″:12}”>Mice with intraperitoneal ID8 ovarian carcinoma or subcutaneous SW1 melanoma were injected with monoclonal antibodies (mAbs) to CD137PD-1CTLA4 7-15 days after tumor initiation. Survival of mice with ID8 tumors tripled and >40% of mice with SW1 tumors remained healthy >150 days after last treatment and are probably cured. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity, required CD4 cells and involved CD8 cells and NK cells to a less extent. The 3 mAb combination significantly decreased CD19 cells at tumor sites, increased IFN-gamma and TNF-alpha producing CD4 and CD8 T cells and mature CD86 dendritic cells (DC), and it increased the ratios of effector CD4 and CD8 T cells to CD4Foxp3 regulatory T (Treg) cells and to CD11bGr-1 myeloid suppressor cells (MDSC). This is consistent with shifting the tumor microenvironment from an immunosuppressive Th2 to an immunostimulatory Th1 type and is further supported by PCR data. Adding an anti-CD19 mAb to the 3 mAb combination in the SW1 model further increased therapeutic efficacy. Data from ongoing experiments show that intratumoral injection of a combination of mAbs to CD137PD-1CTLA4CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity.

in vivo CTLA-4 neutralization
Hooijkaas, A., et al. (2012). "Selective BRAF inhibition decreases tumor-resident lymphocyte frequencies in a mouse model of human melanoma" Oncoimmunology 1(5): 609-617. PubMed

The development of targeted therapies and immunotherapies has markedly advanced the treatment of metastasized melanoma. While treatment with selective BRAF(V600E) inhibitors (like vemurafenib or dabrafenib) leads to high response rates but short response duration, CTLA-4 blocking therapies induce sustained responses, but only in a limited number of patients. The combination of these diametric treatment approaches may further improve survival, but pre-clinical data concerning this approach is limited. We investigated, using Tyr::CreER(T2)PTEN(F-/-)BRAF(F-V600E/+) inducible melanoma mice, whether BRAF(V600E) inhibition can synergize with anti-CTLA-4 mAb treatment, focusing on the interaction between the BRAF(V600E) inhibitor PLX4720 and the immune system. While PLX4720 treatment strongly decreased tumor growth, it did not induce cell death in BRAF(V600E)/PTEN(-/-) melanomas. More strikingly, PLX4720 treatment led to a decreased frequency of tumor-resident T cells, NK-cells, MDSCs and macrophages, which could not be restored by the addition of anti-CTLA-4 mAb. As this effect was not observed upon treatment of BRAF wild-type B16F10 tumors, we conclude that the decreased frequency of immune cells correlates to BRAF(V600E) inhibition in tumor cells and is not due to an off-target effect of PLX4720 on immune cells. Furthermore, anti-CTLA-4 mAb treatment of inducible melanoma mice treated with PLX4720 did not result in enhanced tumor control, while anti-CTLA-4 mAb treatment did improve the effect of tumor-vaccination in B16F10-inoculated mice. Our data suggest that vemurafenib may negatively affect the immune activity within the tumor. Therefore, the potential effect of targeted therapy on the tumor-microenvironment should be taken into consideration in the design of clinical trials combining targeted and immunotherapy.

in vivo CTLA-4 neutralization
Curran, M. A., et al. (2011). "Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production" PLoS One 6(4): e19499. PubMed

BACKGROUND: The co-inhibitory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) attenuates immune responses and prevent autoimmunity, however, tumors exploit this pathway to evade the host T-cell response. The T-cell co-stimulatory receptor 4-1BB is transiently upregulated on T-cells following activation and increases their proliferation and inflammatory cytokine production when engaged. Antibodies which block CTLA-4 or which activate 4-1BB can promote the rejection of some murine tumors, but fail to cure poorly immunogenic tumors like B16 melanoma as single agents. METHODOLOGY/PRINCIPAL FINDINGS: We find that combining alphaCTLA-4 and alpha4-1BB antibodies in the context of a Flt3-ligand, but not a GM-CSF, based B16 melanoma vaccine promoted synergistic levels of tumor rejection. 4-1BB activation elicited strong infiltration of CD8+ T-cells into the tumor and drove the proliferation of these cells, while CTLA-4 blockade did the same for CD4+ effector T-cells. Anti-4-1BB also depressed regulatory T-cell infiltration of tumors. 4-1BB activation strongly stimulated inflammatory cytokine production in the vaccine and tumor draining lymph nodes and in the tumor itself. The addition of CTLA-4 blockade further increased IFN-gamma production from CD4+ effector T-cells in the vaccine draining node and the tumor. Anti 4-1BB treatment, with or without CTLA-4 blockade, induced approximately 75% of CD8+ and 45% of CD4+ effector T-cells in the tumor to express the killer cell lectin-like receptor G1 (KLRG1). Tumors treated with combination antibody therapy showed 1.7-fold greater infiltration by these KLRG1+CD4+ effector T-cells than did those treated with alpha4-1BB alone. CONCLUSIONS/SIGNIFICANCE: This study shows that combining T-cell co-inhibitory blockade with alphaCTLA-4 and active co-stimulation with alpha4-1BB promotes rejection of B16 melanoma in the context of a suitable vaccine. In addition, we identify KLRG1 as a useful marker for monitoring the anti-tumor immune response elicited by this therapy. These findings should aid in the design of future trials for the immunotherapy of melanoma.

in vivo CTLA-4 neutralization
Balachandran, V. P., et al. (2011). "Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido" Nat Med 17(9): 1094-1100. PubMed

Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

    • Mus musculus (House mouse)
    • ,
    • Neuroscience
    • ,
    • Cancer Research
    Conditionally replicative adenovirus as a therapy for malignant peripheral nerve sheath tumors.

    In Molecular Therapy. Oncology on 20 June 2024 by Nikrad, J. A., Galvin, R. T., et al.

    PubMed

    Oncolytic adenoviruses (Ads) stand out as a promising strategy for the targeted infection and lysis of tumor cells, with well-established clinical utility across various malignancies. This study delves into the therapeutic potential of oncolytic Ads in the context of neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). Specifically, we evaluate conditionally replicative adenoviruses (CRAds) driven by the cyclooxygenase 2 (COX2) promoter, as selective agents against MPNSTs, demonstrating their preferential targeting of MPNST cells compared with non-malignant Schwann cell control. COX2-driven CRAds, particularly those with modified fiber-knobs exhibit superior binding affinity toward MPNST cells and demonstrate efficient and preferential replication and lysis of MPNST cells, with minimal impact on non-malignant control cells. In vivo experiments involving intratumoral CRAd injections in immunocompromised mice with human MPNST xenografts significantly extend survival and reduce tumor growth rate compared with controls. Moreover, in immunocompetent mouse models with MPNST-like allografts, CRAd injections induce a robust infiltration of CD8+ T cells into the tumor microenvironment (TME), indicating the potential to promote a pro-inflammatory response. These findings underscore oncolytic Ads as promising, selective, and minimally toxic agents for MPNST therapy, warranting further exploration.

    • Mus musculus (House mouse)
    • ,
    • Immunology and Microbiology
    Combining toll-like receptor agonists with immune checkpoint blockade affects antitumor vaccine efficacy.

    In Journal for Immunotherapy of Cancer on 3 May 2024 by Jeon, D., Hill, E., et al.

    PubMed

    T cell checkpoint receptors are expressed when T cells are activated, and modulation of the expression or signaling of these receptors can alter the function of T cells and their antitumor efficacy. We previously found that T cells activated with cognate antigen had increases in the expression of PD-1, and this was attenuated in the presence of multiple toll-like receptor (TLR) agonists, notably TLR3 plus TLR9. In the current report, we sought to investigate whether combining TLR agonists with immune checkpoint blockade can further augment vaccine-mediated T cell antitumor immunity in murine tumor models. TLR agonists (TLR3 plus TLR9) and immune checkpoint inhibitors (antibodies targeting PD-1, CTLA-4, LAG-3, TIM-3 or VISTA) were combined and delivered with vaccines or vaccine-activated CD8+T cells to E.G7-OVA or MyC-CaP tumor-bearing mice. Tumors were assessed for growth and then collected and analyzed by flow cytometry. Immunization of E.G7-OVA tumor-bearing mice with SIINFEKL peptide vaccine, coadministered with TLR agonists and αCTLA-4, demonstrated greater antitumor efficacy than immunization with TLR agonists or αCTLA-4 alone. Conversely, the antitumor efficacy was abrogated when vaccine and TLR agonists were combined with αPD-1. TLR agonists suppressed PD-1 expression on regulatory T cells (Tregs) and activated this population. Depletion of Tregs in tumor-bearing mice led to greater antitumor efficacy of this combination therapy, even in the presence of αPD-1. Combining vaccination with TLR agonists and αCTLA-4 or αLAG-3 showed greater antitumor than with combinations with αTIM-3 or αVISTA. The combination of TLR agonists and αCTLA-4 or αLAG-3 can further improve the efficacy of a cancer vaccine, an effect not observed using αPD-1 due to activation of Tregs when αPD-1 was combined with TLR3 and TLR9 agonists. These data suggest that optimal combinations of TLR agonists and immune checkpoint blockade may improve the efficacy of human anticancer vaccines. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

    • Cancer Research
    Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.

    In The Journal of Clinical Investigation on 15 December 2023 by Zhao, N., Kabotyanski, E. B., et al.

    PubMed

    Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon (IFN) response uniformly across models. The induction of an IFN response is partially due to the inhibition of Sox4 translation by zotatifin. A similar induction of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Surprisingly, zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened IFN response, resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for zotatifin, and provide a rationale for new combination regimens consisting of zotatifin and chemotherapy or immunotherapy as treatments for TNBC.

    • Cancer Research
    • ,
    • Immunology and Microbiology
    Differential requirements for CD4+ T cells in the efficacy of the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank and brain metastasis models.

    In Journal for Immunotherapy of Cancer on 6 December 2023 by Phadke, M. S., Li, J., et al.

    PubMed

    Although the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations are effective in advanced melanoma, it remains unclear whether their mechanisms of action overlap. We used single cell (sc) RNA-seq, flow cytometry and IHC analysis of responding SM1, D4M-UV2 and B16 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination. CD4+ and CD8+ T cell depletion, tetramer binding assays and ELISPOT assays were used to demonstrate the unique role of CD4+T cell help in the antitumor effects of the anti-PD-1+LAG-3 combination. The anti-PD-1+CTLA-4 combination was associated with the infiltration of FOXP3+regulatory CD4+ cells (Tregs), fewer activated CD4+T cells and the accumulation of a subset of IFNγ secreting cytotoxic CD8+T cells, whereas the anti-PD-1+LAG-3 combination led to the accumulation of CD4+T helper cells that expressed CXCR4, TNFSF8, IL21R and a subset of CD8+T cells with reduced expression of cytotoxic markers. T cell depletion studies showed a requirement for CD4+T cells for the anti-PD-1+LAG-3 combination, but not the PD-1-CTLA-4 combination at both flank and brain tumor sites. In anti-PD-1+LAG-3 treated tumors, CD4+T cell depletion was associated with fewer activated (CD69+) CD8+T cells and impaired IFNγ release but, conversely, increased numbers of activated CD8+T cells and IFNγ release in anti-PD-1+CTLA-4 treated tumors. Together these studies suggest that these two clinically relevant immune checkpoint inhibitor (ICI) combinations have differential effects on CD4+T cell polarization, which in turn, impacted cytotoxic CD8+T cell function. Further insights into the mechanisms of action/resistance of these clinically-relevant ICI combinations will allow therapy to be further personalized. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

    • Cancer Research
    • ,
    • Immunology and Microbiology
    ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer.

    In Nature Communications on 23 November 2023 by Shang, S., Yang, C., et al.

    PubMed

    Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8+ T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated SerpinB2 and CCL4 transcription, two secretory factors responsible for cancer stemness inhibition and CD8+ T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC. © 2023. The Author(s).

    • Mus musculus (House mouse)
    • ,
    • Cancer Research
    Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer.

    In IScience on 20 October 2023 by Freshour, S. L., Chen, T. H., et al.

    PubMed

    To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4+ T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4+ T cell depletion. Functional analysis showed that knocking out IFNgR1 in endothelial cells inhibited treatment response. Together, these results indicated that IFN-g signaling in endothelial cells is a key mediator of ICB induced anti-tumor activity. © 2023 The Authors.

    • Mus musculus (House mouse)
    • ,
    • Cancer Research
    A surgically optimized intraoperative poly(I:C)-releasing hydrogel prevents cancer recurrence.

    In Cell Reports Medicine on 18 July 2023 by Rwandamuriye, F. X., Evans, C. W., et al.

    PubMed

    Recurrences frequently occur following surgical removal of primary tumors. In many cancers, adjuvant therapies have limited efficacy. Surgery provides access to the tumor microenvironment, creating an opportunity for local therapy, in particular immunotherapy, which can induce local and systemic anti-cancer effects. Here, we develop a surgically optimized biodegradable hyaluronic acid-based hydrogel for sustained intraoperative delivery of Toll-like receptor 3 agonist poly(I:C) and demonstrate that it significantly reduces tumor recurrence after surgery in multiple mouse models. Mechanistically, poly(I:C) induces a transient interferon alpha (IFNα) response, reshaping the tumor/wound microenvironment by attracting inflammatory monocytes and depleting regulatory T cells. We demonstrate that a pre-existing IFN signature predicts response to the poly(I:C) hydrogel, which sensitizes tumors to immune checkpoint therapy. The safety, immunogenicity, and surgical feasibility are confirmed in a veterinary trial in canine soft tissue tumors. The surgically optimized poly(I:C)-loaded hydrogel provides a safe and effective approach to prevent cancer recurrence. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

    • Immunology and Microbiology
    TSLP/dendritic cell axis promotes CD4+ T cell tolerance to the gut microbiome.

    In JCI Insight on 10 July 2023 by Messerschmidt, J. L., Azin, M., et al.

    PubMed

    Thymic stromal lymphopoietin (TSLP) overexpression is widely associated with atopy. However, TSLP is expressed in normal barrier organs, suggesting a homeostatic function. To determine the function of TSLP in barrier sites, we investigated the impact of endogenous TSLP signaling on the homeostatic expansion of CD4+ T cells in adult mice. Surprisingly, incoming CD4+ T cells induced lethal colitis in adult Rag1-knockout animals that lacked the TSLP receptor (Rag1KOTslprKO). Endogenous TSLP signaling was required for reduced CD4+ T cell proliferation, Treg differentiation, and homeostatic cytokine production. CD4+ T cell expansion in Rag1KOTslprKO mice was dependent on the gut microbiome. The lethal colitis was rescued by parabiosis between Rag1KOTslprKO and Rag1KO animals and wild-type dendritic cells (DCs) suppressed CD4+ T cell-induced colitis in Rag1KOTslprKO mice. A compromised T cell tolerance was noted in TslprKO adult colon, which was exacerbated by anti-PD-1 and anti-CTLA-4 therapy. These results reveal a critical peripheral tolerance axis between TSLP and DCs in the colon that blocks CD4+ T cell activation against the commensal gut microbiome.

    • Mus musculus (House mouse)
    • ,
    • Cancer Research
    • ,
    • Immunology and Microbiology
    Soluble CTLA-4 raises the threshold for T-cell activation and modulates anti-tumour immunity

    Preprint on BioRxiv : the Preprint Server for Biology on 7 June 2023 by Kennedy, P. T., Saulters, E. L., et al.

    PubMed

    CTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumour control. Antibodies targeting CTLA-4 have been promising treatment for numerous cancers, but the mechanistic basis of their anti-tumoral immune boosting effects are poorly understood. Although the ctla4 gene also encodes an alternatively-spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in murine cancer model. We show that expression of sCTLA-4 in tumour cells suppresses CD8 + T-cells in vitro , and accelerates growth and experimental metastasis of murine tumours in vivo . These effects were accompanied by modification of the immune infiltrate, notably restraining CD8 + T-cells in a non-effector state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoural CD8 + T-cell activation and cytolytic potential, correlating with therapeutic efficacy and tumour control. This previously unappreciated role of sCTLA-4 suggests that better understanding of the biology and function of multi-gene products of immune checkpoint receptors needs to be fully elucidated for improved cancer immunotherapy.

    • Immunology and Microbiology
    Acidity-mediated induction of FoxP3+ regulatory T cells.

    In European Journal of Immunology on 1 June 2023 by Rao, D., Stunnenberg, J. A., et al.

    PubMed

    Glucose limitation and increased lactic acid levels are consequences of the elevated glycolytic activity of tumor cells, and constitute a metabolic barrier for the function of tumor infiltrating effector immune cells. The immune-suppressive functions of regulatory T cells (Tregs) are unobstructed in lactic-acid rich environments. However, the impact of lactic acid on the induction of Tregs remains unknown. We observed increased TGFβ-mediated induction of Forkhead box P3+ (FoxP3+ ) cells in the presence of extracellular lactic acid, in a glycolysis-independent, acidity-dependent manner. These CD4+ FoxP3+ cells expressed Treg-associated markers, including increased expression of CD39, and were capable of exerting suppressive functions. Corroborating these results in vivo, we observed that neutralizing the tumor pH by systemic administration of sodium bicarbonate (NaBi) decreased Treg abundance. We conclude that acidity augments Treg induction and propose that therapeutic targeting of acidity in the tumor microenvironment (TME) might reduce Treg-mediated immune suppression within tumors. © 2023 Wiley-VCH GmbH.

    • Mus musculus (House mouse)
    • ,
    • Immunology and Microbiology
    Clonally expanded, thyrotoxic effector CD8+ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

    In Science Translational Medicine on 17 May 2023 by Lechner, M. G., Zhou, Z., et al.

    PubMed

    Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells (effector CD8+ T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (TFH) and T peripheral helper (TPH) cells, as a driver of these thyrotoxic effector CD8+ T cells. In the presence of IL-21, human CD8+ T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.

    • Cancer Research
    Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal.

    In Cell Stem Cell on 4 May 2023 by Hao, X., Shen, Y., et al.

    PubMed

    Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitor (OP) expansion, hematopoietic stem cell dislocation, and CD41- granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41- GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in the hematopoietic program. Importantly, these effects persist post-surgery and continue to impair anti-tumor immunity. Conditional knockout or inhibition of MMP-13 accelerates immune reinstatement and restores the efficacies of immunotherapies. Therefore, tumor-induced systemic effects are initiated by OP-GMP crosstalk that outlasts tumor burden, and additional treatment is required to reverse these effects for optimal therapeutic efficacy. Copyright © 2023 Elsevier Inc. All rights reserved.

    • Cancer Research
    IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma.

    In The Journal of Experimental Medicine on 1 May 2023 by Reijers, I. L. M., Rao, D., et al.

    PubMed

    Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies. © 2023 Reijers et al.

    • Immunology and Microbiology
    • ,
    • Cell Biology
    Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.

    In Cell on 27 April 2023 by Bender, M. J., McPherson, A. C., et al.

    PubMed

    The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients. Copyright © 2023 Elsevier Inc. All rights reserved.

    • Mus musculus (House mouse)
    Micro-abnormalities in the retina and choroid induced by anti-CTLA4 treatment.

    In Scientific Reports on 18 April 2023 by Mukai, R., Tajika, Y., et al.

    PubMed

    Anti-Cytotoxic T-Lymphocyte Associated protein 4 agents, such as ipilimumab, are widely applied to various cancers. However, they cause immune-related adverse effects throughout the body, including the eye. This study examined whether ipilimumab induces retinal and choroidal abnormalities in rodents, and investigated potential underlying mechanisms. Female wild-type mice were injected with ipilimumab three times/week for 5 weeks. The mice underwent optical coherence tomography (OCT) on the first day of the 6th week. Retinal function and morphology were evaluated by light microscopy, immunohistochemistry and electroretinography (ERG). On OCT, the lines indicating the ellipsoid and interdigitation were obscure in treated mice, suggesting outer retina destruction. Haematoxylin-eosin staining revealed destruction, shortening, and outer segment vacuolization. Treated mice exhibited weaker, fragmented rhodamine peanut agglutinin staining in outer photoreceptor structures. The choroid of treated mice showed severe infiltration of CD45-positive cells. In addition, CD8-positive cells invaded into the outer retina. On ERG, rod, maximum responses of combined rods and cones, and cone response wave amplitudes were significantly reduced in treated mice. Ipilimumab may induce impairments in outer photoreceptor architecture accompanied with CD8- positive infiltration in the retina and CD45-positive cell infiltration in the choroid, which may contribute to retinal function deterioration. © 2023. The Author(s).

    • Mus musculus (House mouse)
    • ,
    • Cancer Research
    • ,
    • Immunology and Microbiology
    A neutrophil response linked to tumor control in immunotherapy.

    In Cell on 30 March 2023 by Gungabeesoon, J., Gort-Freitas, N. A., et al.

    PubMed

    Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. Here, we investigate the role of neutrophils in immunotherapy, leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sellhi state rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of anti-tumor immunity, including BATF3-dependent DCs, IL-12, and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy. Copyright © 2023 Elsevier Inc. All rights reserved.

    • Mus musculus (House mouse)
    • ,
    • Cancer Research
    • ,
    • Immunology and Microbiology
    IFNγ is a central node of cancer immune equilibrium.

    In Cell Reports on 28 March 2023 by Walsh, M. J., Stump, C. T., et al.

    PubMed

    Tumors in immune equilibrium are held in balance between outgrowth and destruction by the immune system. The equilibrium phase defines the duration of clinical remission and stable disease, and escape from equilibrium remains a major clinical problem. Using a non-replicating HSV-1 vector expressing interleukin-12 (d106S-IL12), we developed a mouse model of therapy-induced immune equilibrium, a phenomenon previously seen only in humans. This immune equilibrium was centrally reliant on interferon-γ (IFNγ). CD8+ T cell direct recognition of MHC class I, perforin/granzyme-mediated cytotoxicity, and extrinsic death receptor signaling such as Fas/FasL were all individually dispensable for equilibrium. IFNγ was critically important and played redundant roles in host and tumor cells such that IFNγ sensing in either compartment was sufficient for immune equilibrium. We propose that these redundant mechanisms of action are integrated by IFNγ to protect from oncogenic or chronic viral threats and establish IFNγ as a central node in therapy-induced immune equilibrium. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

    • Cancer Research
    • ,
    • Mus musculus (House mouse)
    Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer.

    In Nature Communications on 22 March 2023 by Cotto, K. C., Feng, Y. Y., et al.

    PubMed

    Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, and open-source software package designed to integrate somatic variants from genomic data with splice junctions from bulk or single cell transcriptomic data to identify variants that may cause aberrant splicing. We apply RegTools to over 9000 tumor samples with both tumor DNA and RNA sequence data. RegTools discovers 235,778 events where a splice-associated variant significantly increases the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotate them with the Variant Effect Predictor, SpliceAI, and Genotype-Tissue Expression junction counts and compare our results to other tools that integrate genomic and transcriptomic data. While many events are corroborated by the aforementioned tools, the flexibility of RegTools also allows us to identify splice-associated variants in known cancer drivers, such as TP53, CDKN2A, and B2M, and other genes. © 2023. The Author(s).

    • Cancer Research
    • ,
    • Immunology and Microbiology
    Hyperthermia combined with immune checkpoint inhibitor therapy: Synergistic sensitization and clinical outcomes.

    In Cancer Medicine on 1 February 2023 by Liu, P., Ye, M., et al.

    PubMed

    Within the field of oncotherapy, research interest regarding immunotherapy has risen to the point that it is now seen as a key application. However, inherent disadvantages of immune checkpoint inhibitors (ICIs), such as their low response rates and immune-related adverse events (irAEs), currently restrict their clinical application. Were these disadvantages to be overcome, more patients could derive prolonged benefits from ICIs. At present, many basic experiments and clinical studies using hyperthermia combined with ICI treatment (HIT) have been performed and shown the potential to address the above challenges. Therefore, this review extensively summarizes the knowledge and progress of HIT for analysis and discusses the effect and feasibility. In this review, we explored the PubMed and clinicaltrials.gov databases, with regard to the searching terms "immune checkpoint inhibitor, immunotherapy, hyperthermia, ablation, photothermal therapy". By reviewing the literature, we analyzed how hyperthermia influences tumor immunology and improves the efficacy of ICI. Hyperthermia can trigger a series of multifactorial molecular cascade reactions between tumors and immunization and can significantly induce cytological modifications within the tumor microenvironment (TME). The pharmacological potency of ICIs can be enhanced greatly through the immunomodulatory amelioration of immunosuppression, and the activation of immunostimulation. Emerging clinical trials outcome regarding HIT have verified and enriched the theoretical foundation of synergistic sensitization. HIT research is now starting to transition from preclinical studies to clinical investigations. Several HIT sensitization mechanisms have been reflected and demonstrated as significant survival benefits for patients through pioneering clinical trials. Further studies into the theoretical basis and practical standards of HIT, combined with larger-scale clinical studies involving more cancer types, will be necessary for the future. © 2022 The Authors. Cancer Medicine published by John Wiley Sons Ltd.

    • Mus musculus (House mouse)
    • ,
    • Cancer Research
    • ,
    • Immunology and Microbiology
    Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation.

    In Nature Communications on 17 January 2023 by Lin, W., Chen, L., et al.

    PubMed

    The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic YTHDF1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. Additionally, YTHDF1 deficiency converts cold tumors into responsive hot tumors, which improves ICI efficacy. Mechanistically, YTHDF1 deficiency inhibits the translation of lysosomal genes and limits lysosomal proteolysis of the major histocompatibility complex class I (MHC-I) and antigens, ultimately restoring tumor immune surveillance. In addition, we design a system for exosome-mediated CRISPR/Cas9 delivery to target YTHDF1 in vivo, resulting in YTHDF1 depletion and antitumor activity. Our findings elucidate the role of tumor-intrinsic YTHDF1 in driving immune evasion and its underlying mechanism. © 2023. The Author(s).

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