InVivoMAb anti-human PD-1 (CD279)
Product Details
The J116 monoclonal antibody reacts with human PD-1 (programmed death-1) also known as CD279. PD-1 is a 50-55 kDa cell surface receptor encoded by the Pdcd1 gene that belongs to the CD28 family of the Ig superfamily. PD-1 is transiently expressed on CD4 and CD8 thymocytes as well as activated T and B lymphocytes and myeloid cells. PD-1 expression declines after successful elimination of antigen. Additionally, Pdcd1 mRNA is expressed in developing B lymphocytes during the pro-B-cell stage. PD-1’s structure includes a ITIM (immunoreceptor tyrosine-based inhibitory motif) suggesting that PD-1 negatively regulates TCR signals. PD-1 signals via binding its two ligands, PD-L1 and PD-L2 both members of the B7 family. Upon ligand binding, PD-1 signaling inhibits T-cell activation, leading to reduced proliferation, cytokine production, and T cell death. Additionally, PD-1 is known to play key roles in peripheral tolerance and prevention of autoimmune disease in mice as PD-1 knockout animals show dilated cardiomyopathy, splenomegaly, and loss of peripheral tolerance. Induced PD-L1 expression is common in many tumors including squamous cell carcinoma, colon adenocarcinoma, and breast adenocarcinoma. PD-L1 overexpression results in increased resistance of tumor cells to CD8 T cell mediated lysis. In mouse models of melanoma, tumor growth can be transiently arrested via treatment with antibodies which block the interaction between PD-L1 and its receptor PD-1. For these reasons anti-PD-1 mediated immunotherapies are currently being explored as cancer treatments. Binding of the J116 antibody is reported to inhibit PD-1 signal transduction, however, it is not reported to block PD-L1 binding.Specifications
| Isotype | Mouse IgG1,Ā Īŗ |
|---|---|
| Recommended Isotype Control(s) | InVivoMAb mouse IgG1 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 vitro PD-1 neutralization in vivo PD-1 blockade in humanized mice |
| Formulation |
PBS, pH 7.0 Contains no stabilizers or preservatives |
| Endotoxin |
<2EU/mg (<0.002EU/Ī¼g) Determined by LAL gel clotting assay |
| Purity |
>95% Determined by SDS-PAGE |
| Sterility | 0.2 Āµm filtration |
| Production | Purified from cell culture supernatant in an animal-free facility |
| Purification | Protein G |
| RRID | AB_10950318 |
| Molecular Weight | 150 kDa |
| Storage | The antibody solution should be stored at the stock concentration at 4Ā°C. Do not freeze. |
Recommended Products
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Recommended Isotype Control(s)
InVivoMAb mouse IgG1 isotype control, unknown specificity
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Recommended Dilution Buffer
InVivoPure pH 7.0 Dilution Buffer
in vitro PD-1 neutralization
Tkachev, V., et al. (2015). "Programmed death-1 controls T cell survival by regulating oxidative metabolism" J Immunol 194(12): 5789-5800. PubMed
The coinhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly upregulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1(Hi)ROS(Hi) phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels, and PD-1-driven increases in ROS were dependent upon the oxidation of fatty acids, because treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by antioxidants. Furthermore, PD-1-driven changes in ROS were fundamental to establishing a cellās susceptibility to subsequent metabolic inhibition, because blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing ROS in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.
in vivo PD-1 blockade in humanized mice
Tsukahara, T., et al. (2015). "The Tol2 transposon system mediates the genetic engineering of T-cells with CD19-specific chimeric antigen receptors for B-cell malignancies" Gene Ther 22(2): 209-215. PubMed
Engineered T-cell therapy using a CD19-specific chimeric antigen receptor (CD19-CAR) is a promising strategy for the treatment of advanced B-cell malignancies. Gene transfer of CARs to T-cells has widely relied on retroviral vectors, but transposon-based gene transfer has recently emerged as a suitable nonviral method to mediate stable transgene expression. The advantages of transposon vectors compared with viral vectors include their simplicity and cost-effectiveness. We used the Tol2 transposon system to stably transfer CD19-CAR into human T-cells. Normal human peripheral blood lymphocytes were co-nucleofected with the Tol2 transposon donor plasmid carrying CD19-CAR and the transposase expression plasmid and were selectively propagated on NIH3T3 cells expressing human CD19. Expanded CD3(+) T-cells with stable and high-level transgene expression (~95%) produced interferon-gamma upon stimulation with CD19 and specifically lysed Raji cells, a CD19(+) human B-cell lymphoma cell line. Adoptive transfer of these T-cells suppressed tumor progression in Raji tumor-bearing Rag2(-/-)gammac(-/-) immunodeficient mice compared with control mice. These results demonstrate that the Tol2 transposon system could be used to express CD19-CAR in genetically engineered T-cells for the treatment of refractory B-cell malignancies.
in vivo PD-1 blockade in humanized mice
Wang, C., et al. (2013). "Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells" J Clin Invest 123(4): 1677-1693. PubMed
Human graft endothelial cells (ECs) can act as antigen-presenting cells to initiate allograft rejection by host memory T cells. Rapamycin, an mTOR inhibitor used clinically to suppress T cell responses, also acts on DCs, rendering them tolerogenic. Here, we report the effects of rapamycin on EC alloimmunogenicity. Compared with mock-treated cells, rapamycin-pretreated human ECs (rapa-ECs) stimulated less proliferation and cytokine secretion from allogeneic CD4+ memory cells, an effect mimicked by shRNA knockdown of mTOR or raptor in ECs. The effects of rapamycin persisted for several days and were linked to upregulation of the inhibitory molecules PD-L1 and PD-L2 on rapa-ECs. Additionally, rapa-ECs produced lower levels of the inflammatory cytokine IL-6. CD4+ memory cells activated by allogeneic rapa-ECs became hyporesponsive to restimulation in an alloantigen-specific manner and contained higher percentages of suppressive CD4+CD25(hi)CD127(lo)FoxP3+ cells that did not produce effector cytokines. In a human-mouse chimeric model of allograft rejection, rapamycin pretreatment of human arterial allografts increased graft EC expression of PD-L1 and PD-L2 and reduced subsequent infiltration of allogeneic effector T cells into the artery intima and intimal expansion. Preoperative conditioning of allograft ECs with rapamycin could potentially reduce immune-mediated rejection.
in vitro PD-1 neutralization
Singh, A., et al. (2012). "Foxp3+ regulatory T cells among tuberculosis patients: impact on prognosis and restoration of antigen specific IFN-gamma producing T cells" PLoS One 7(9): e44728. PubMed
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) and programmed death-1 (PD-1) molecules have emerged as pivotal players in immune suppression of chronic diseases. However, their impact on the disease severity, therapeutic response and restoration of immune response in human tuberculosis remains unclear. Here, we describe the possible role of Treg cells, their M. tuberculosis driven expansion and contribution of PD-1 pathway to the suppressive function of Treg cells among pulmonary tuberculosis (PTB) patients. Multicolor flow cytometry, cell culture, cells sorting and ELISA were employed to execute the study. Our results showed significant increase in frequency of antigen-reactive Treg cells, which gradually declined during successful therapy and paralleled with decline of M. tuberculosis-specific IL-10 along with elevation of IFN-gamma production, and raising the IFN-gamma/IL-4 ratio. Interestingly, persistence of Treg cells tightly correlated with MDR tuberculosis. Also, we show that blocking PD-1/PD-L1 pathway abrogates Treg-mediated suppression, suggesting that the PD-1/PD-L1 pathway is required for Treg-mediated suppression of the antigen-specific T cells. Treg cells possibly play a role in dampening the effector immune response and abrogating PD-1 pathway on Treg cells significantly rescued protective T cell response, suggesting its importance in immune restoration among tuberculosis patients.
in vitro PD-1 neutralization
Rosignoli, G., et al. (2009). "Programmed death (PD)-1 molecule and its ligand PD-L1 distribution among memory CD4 and CD8 T cell subsets in human immunodeficiency virus-1-infected individuals" Clin Exp Immunol 157(1): 90-97. PubMed
Human immunodeficiency virus (HIV)-1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti-HIV-1-specific responses: programmed death (PD)-1 molecule and its ligand PD-L1 are negative regulators of T cell activity and their expression is increased during HIV-1 infection. This study examines correlations between T cell maturation, expression of PD-1 and PD-L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV-1(+) and 17 uninfected individuals were phenotyped for PD-1 and PD-L1 expression on CD4(+) and CD8(+) T cell subsets. The effect of PD-1 and PD-L1 blockade on proliferation and interferon (IFN)-gamma production was tested on eight HIV-1(+) patients. Naive (CCR7(+)CD45RA(+)) CD8(+) T cells were reduced in HIV-1 aviraemic (P = 0.0065) and viraemic patients (P = 0.0130); CD8 T effector memory subsets [CCR7(-)CD45RA(-)(T(EM))] were increased in HIV-1(+) aviraemic (P = 0.0122) and viraemic (P = 0.0023) individuals versus controls. PD-1 expression was increased in CD4 naive (P = 0.0496), central memory [CCR7(+)CD45RA(-) (T(CM)); P = 0.0116], T(EM) (P = 0.0037) and CD8 naive T cells (P = 0.0133) of aviraemic HIV-1(+) versus controls. PD-L1 was increased in CD4 T(EMRA) (CCR7(-)CD45RA(+), P = 0.0119), CD8 T(EM) (P = 0.0494) and CD8 T(EMRA) (P = 0.0282) of aviraemic HIV-1(+)versus controls. PD-1 blockade increased HIV-1-specific proliferative responses in one of eight patients, whereas PD-L1 blockade restored responses in four of eight patients, but did not increase IFN-gamma-production. Alteration of T cell subsets, accompanied by increased PD-1 and PD-L1 expression in HIV-1 infection contributes to anergy and impaired anti-HIV-1-specific responses which are not rescued when PD-1 is blocked, in contrast to when PD-L1 is blocked, due possibly to an ability to bind to receptors other than PD-1.
in vitro PD-1 neutralization
urado, J. O., et al. (2008). "Programmed death (PD)-1:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis" J Immunol 181(1): 116-125. PubMed
Protective immunity against Mycobacterium tuberculosis requires the generation of cell-mediated immunity. We investigated the expression and role of programmed death 1 (PD-1) and its ligands, molecules known to modulate T cell activation, in the regulation of IFN-gamma production and lytic degranulation during human tuberculosis. We demonstrated that specific Ag-stimulation increased CD3+PD-1+ lymphocytes in peripheral blood and pleural fluid from tuberculosis patients in direct correlation with IFN-gamma production from these individuals. Moreover, M. tuberculosis-induced IFN-gamma participated in the up-regulation of PD-1 expression. Blockage of PD-1 or PD-1 and its ligands (PD-Ls: PD-L1, PD-L2) enhanced the specific degranulation of CD8+ T cells and the percentage of specific IFN-gamma-producing lymphocytes against the pathogen, demonstrating that the PD-1:PD-Ls pathway inhibits T cell effector functions during active M. tuberculosis infection. Furthermore, the simultaneous blockage of the inhibitory receptor PD-1 together with the activation of the costimulatory protein signaling lymphocytic activation molecule led to the promotion of protective IFN-gamma responses to M. tuberculosis, even in patients with weak cell-mediated immunity against the bacteria. Together, we demonstrated that PD-1 interferes with T cell effector functions against M. tuberculosis, suggesting that PD-1 has a key regulatory role during the immune response of the host to the pathogen.
- Cancer Research,
Humanized mouse models of KRAS-mutated colorectal and pancreatic cancers with HLA-class-I match for pre-clinical evaluation of cancer immunotherapies.
In Oncoimmunology on 1 December 2025 by DƔvola, M. E., Cormier, O., et al.
PubMed
Cancer immunotherapy promises to treat challenging cancers including KRAS-mutated colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). However, pre-clinical animal models that better mimic patient tumor and immune system interactions are required. While humanized mice are promising vehicles for pre-clinical immunotherapy testing, currently used cancer models retain limitations, such as lack of a human thymus for human leukocyte antigen (HLA)-based education of human T cells. As cytotoxic T lymphocyte (CTL) activity underlies many immunotherapies, we developed more clinically relevant KRAS-mutated CRC and PDAC humanized cancer models using transgenic NRG-A2 mice expressing HLA-A2.1 to enable HLA-class-I match between mouse tissues (including the thymus), the humanized immune system and human tumors. Using these novel humanized cancer models and a CTL-mediated combination (immuno)therapy with clinical potential, we were able to recapitulate the complexity and therapy-induced changes reported in patient biopsies, demonstrating the use of these HLA-matched models for pre-clinical validation of novel immunotherapies.
- Cancer Research,
- Immunology and Microbiology
Enhancing T-cell recruitment in renal cell carcinoma with cytokine-armed adenoviruses.
In Oncoimmunology on 1 October 2024 by Feodoroff, M., Hamdan, F., et al.
PubMed
Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, in vivo humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.
- Cancer Research,
- Cell Biology
Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling.
In Sci Adv on 19 January 2024 by Martins, C., Rasbach, E., et al.
PubMed
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.
- Cell Biology,
- Immunology and Microbiology
Genome scale CRISPR screens identify actin capping proteins as key modulators of therapeutic responses to radiation and immunotherapy
In bioRxiv on 15 January 2024 by Verma, N., Renauer, P. A., et al.
- Immunology and Microbiology,
- Cancer Research
Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade.
In Clin Cancer Res on 1 August 2023 by Hong, D. C., Yang, J., et al.
PubMed
Radiation-induced sarcomas (RIS) have a poor prognosis and lack effective treatments. Its genome and tumor microenvironment are not well characterized and need further exploration.
- Biochemistry and Molecular biology,
- Cell Biology,
- Immunology and Microbiology
Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.
In Front Oncol on 14 February 2023 by Babl, N., Hofbauer, J., et al.
PubMed
The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro.
- Cancer Research,
- Immunology and Microbiology
Preclinical Platform Using a Triple-negative Breast Cancer Syngeneic Murine Model to Evaluate Immune Checkpoint Inhibitors.
In Anticancer Res on 1 January 2023 by Katuwal, N. B., Park, N., et al.
PubMed
To evaluate the feasibility of syngeneic mouse models of breast cancer by analyzing the efficacy of immune checkpoint inhibitors (ICIs) and potential predictive biomarkers.
- Cancer Research,
- Immunology and Microbiology
FGFR4-Targeted Chimeric Antigen Receptors Combined with Anti-Myeloid Polypharmacy Effectively Treat Orthotopic Rhabdomyosarcoma.
In Mol Cancer Ther on 7 October 2022 by Sullivan, P. M., Kumar, R., et al.
PubMed
Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. Treatment outcomes, particularly for relapsed/refractory or metastatic disease, have not improved in decades. The current lack of novel therapies and low tumor mutational burden suggest that chimeric antigen receptor (CAR) T-cell therapy could be a promising approach to treating RMS. Previous work identified FGF receptor 4 (FGFR4, CD334) as being specifically upregulated in RMS, making it a candidate target for CAR T cells. We tested the feasibility of an FGFR4-targeted CAR for treating RMS using an NSG mouse with RH30 orthotopic (intramuscular) tumors. The first barrier we noted was that RMS tumors produce a collagen-rich stroma, replete with immunosuppressive myeloid cells, when T-cell therapy is initiated. This stromal response is not seen in tumor-only xenografts. When scFV-based binders were selected from phage display, CARs targeting FGFR4 were not effective until our screening approach was refined to identify binders to the membrane-proximal domain of FGFR4. Having improved the CAR, we devised a pharmacologic strategy to augment CAR T-cell activity by inhibiting the myeloid component of the T-cell-induced tumor stroma. The combined treatment of mice with anti-myeloid polypharmacy (targeting CSF1R, IDO1, iNOS, TGFbeta, PDL1, MIF, and myeloid misdifferentiation) allowed FGFR4 CAR T cells to successfully clear orthotopic RMS tumors, demonstrating that RMS tumors, even with very low copy-number targets, can be targeted by CAR T cells upon reversal of an immunosuppressive microenvironment.
- Immunology and Microbiology
Targeting cathepsin B by cycloastragenol enhances antitumor immunity of CD8 T cells via inhibiting MHC-I degradation.
In J Immunother Cancer on 1 October 2022 by Deng, G., Zhou, L., et al.
PubMed
The loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in Astragalus membranaceus, has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear.
- Cancer Research,
- Immunology and Microbiology
Preclinical platform using a triple-negative breast cancer syngeneic murine model to evaluate immune checkpoint inhibitors
In Research Square on 8 September 2022 by Bahadur, N. B., Park, N., et al.
- Cancer Research,
- Immunology and Microbiology
Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-Ī² type II receptor signaling.
In Nat Commun on 1 August 2022 by Xie, F., Zhou, X., et al.
PubMed
Cancer immunotherapies have shown clinical success in various types of tumors but the patient response rate is low, particularly in breast cancer. Here we report that malignant breast cancer cells can transfer active TGF-Ī² type II receptor (TĪ²RII) via tumor-derived extracellular vesicles (TEV) and thereby stimulate TGF-Ī² signaling in recipient cells. Up-take of extracellular vesicle-TĪ²RII (EV-TĪ²RII) in low-grade tumor cells initiates epithelial-to-mesenchymal transition (EMT), thus reinforcing cancer stemness and increasing metastasis in intracardial xenograft and orthotopic transplantation models. EV-TĪ²RII delivered as cargo to CD8+ T cells induces the activation of SMAD3 which we demonstrated to associate and cooperate with TCF1 transcription factor to impose CD8+ T cell exhaustion, resulting in failure of immunotherapy. The levels of TĪ²RII+ circulating extracellular vesicles (crEV) appears to correlate with tumor burden, metastasis and patient survival, thereby serve as a non-invasive screening tool to detect malignant breast tumor stages. Thus, our findings not only identify a possible mechanism by which breast cancer cells can promote T cell exhaustion and dampen host anti-tumor immunity, but may also identify a target for immune therapy against the most devastating breast tumors.
- Biochemistry and Molecular biology,
- Cancer Research,
- Cell Biology
IFNĪ± Potentiates Anti-PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment.
In Cancer Discov on 6 July 2022 by Hu, B., Yu, M., et al.
PubMed
The overall response rate for anti-PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of IFNĪ± and anti-PD-1-based immunotherapy resulted in enhanced antitumor activity in patients with unresectable HCC. In both immunocompetent orthotopic and spontaneous HCC models, IFNĪ± therapy synergized with anti-PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+CD8+ T cells. Mechanistically, IFNĪ± suppressed HIF1Ī± signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing a high-glucose microenvironment that fostered transcription of the T-cell costimulatory molecule Cd27 via mTOR-FOXM1 signaling in infiltrating CD8+ T cells. Together, these data reveal that IFNĪ± reprograms glucose metabolism within the HCC tumor microenvironment, thereby liberating T-cell cytotoxic capacities and potentiating the PD-1 blockade-induced immune response. Our findings suggest that IFNĪ± and anti-PD-1 cotreatment is an effective novel combination strategy for patients with HCC.
- Immunohistochemistry,
- Mus musculus (Mouse),
- Cancer Research,
- Immunology and Microbiology,
- Immunohistochemistry,
- Immunohistochemistry,
- Immunohistochemistry
Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer.
In J Transl Med on 21 June 2022 by Liu, L., Wang, A., et al.
PubMed
TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer.
- Cancer Research,
- Immunology and Microbiology
Blocking TIGIT/CD155 Signal Reverses CD8+T Cell Exhaustion and Enhances the Anti-Tumor Ability of Cervical Cancer
In Research Square on 28 February 2022 by Liu, L., Wang, A., et al.
- Cancer Research,
- Immunology and Microbiology
T cells drive negative feedback mechanisms in cancer associated fibroblasts, promoting expression of co-inhibitory ligands, CD73 and IL-27 in non-small cell lung cancer.
In Oncoimmunology on 23 July 2021 by O'Connor, R. A., Chauhan, V., et al.
PubMed
The success of immune checkpoint therapy shows tumor-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumor micro-environment (TME). Cancer associated fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localize with T cells in non-small cell lung cancer. We demonstrate the bidirectional nature of CAF/T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bidirectional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells.
- Cancer Research,
- Immunology and Microbiology
Integrin Ī±vĪ²6-TGFĪ²-SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer.
In Cancer Cell on 11 January 2021 by Bagati, A., Kumar, S., et al.
PubMed
Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to TĀ cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin Ī±vĪ²6 receptor on the surface of tumor cells, which activates TGFĪ² from a latent precursor. An integrin Ī±vĪ²6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic TĀ cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin Ī±vĪ²6-TGFĪ²-SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin.
- Homo sapiens (Human)
Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model.
In J Immunother Cancer on 1 November 2020 by Park, N., Pandey, K., et al.
PubMed
Well-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.
- Immunology and Microbiology
In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy.
In J Immunother Cancer on 1 October 2020 by Cheng, Y., Lemke-Miltner, C. D., et al.
PubMed
CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. In situ vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading to type I interferon secretion and tumor antigen presentation to T cells and systemic antitumor T cell responses. This study is designed to investigate if CMP-001 would enhance head and neck squamous cell carcinoma (HNSCC) tumor response to anti-programmed cell death protein-1 (anti-PD-1) therapy in a human papilloma virus-positive (HPV+) tumor mouse model.
- Cancer Research,
- Cell Biology,
- Immunology and Microbiology
Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma.
In JCI Insight on 15 June 2017 by Siska, P. J., Beckermann, K. E., et al.
PubMed
Cancer cells can inhibit effector T cells (Teff) through both immunomodulatory receptors and the impact of cancer metabolism on the tumor microenvironment. Indeed, Teff require high rates of glucose metabolism, and consumption of essential nutrients or generation of waste products by tumor cells may impede essential T cell metabolic pathways. Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the tumor suppressor von Hippel-Lindau (VHL) and altered cancer cell metabolism. Here, we assessed how ccRCC influences the metabolism and activation of primary patient ccRCC tumor infiltrating lymphocytes (TIL). CD8 TIL were abundant in ccRCC, but they were phenotypically distinct and both functionally and metabolically impaired. ccRCC CD8 TIL were unable to efficiently uptake glucose or perform glycolysis and had small, fragmented mitochondria that were hyperpolarized and generated large amounts of ROS. Elevated ROS was associated with downregulated mitochondrial SOD2. CD8 T cells with hyperpolarized mitochondria were also visible in the blood of ccRCC patients. Importantly, provision of pyruvate to bypass glycolytic defects or scavengers to neutralize mitochondrial ROS could partially restore TIL activation. Thus, strategies to improve metabolic function of ccRCC CD8 TIL may promote the immune response to ccRCC.
