InVivoPlus anti-mouse PD-1 (CD279)

Immunotherapy has emerged as a promising therapeutic option for cancer management, but its applicability in patients with triple-negative breast cancer (TNBC) is limited by the low efficacy due to the immunosuppressive tumor microenvironment (TME). Here, we identify lysine demethylase 3B (KDM3B) as an essential mediator of immune evasion in TNBC. KDM3B expression is negatively correlated with cytotoxic T lymphocyte (CTL) infiltration. Genetic or pharmacologic inhibition of KDM3B facilitates the recruitment and activation of CD8+ T cells, thereby suppressing tumor growth in TNBC mouse models. Mechanistically, KDM3B targets SHP1 by reducing H3K9me2 levels at its promoter. Suppression of KDM3B attenuates SHP1-mediated STING inactivation, which triggers robust type I interferon (IFN) responses. Strikingly, both KDM3B depletion and treatment with the KDM3B-selective inhibitor P3FI-90 significantly suppresses tumor progression and mitigates resistance to immune checkpoint blockade (ICB) therapy. Taken together, these findings establish KDM3B as a key regulator of immune escape, and targeting KDM3B represents a promising strategy to augment the efficacy of immunotherapy for TNBC.

Cancer-associated mesothelial cells (CAMCs) are key modulators of the ovarian tumor microenvironment, contributing to tumor growth and immune evasion. Mesothelial cells (MCs) maintain peritoneal homeostasis and immune surveillance and represent the first point of contact during abdominal dissemination of ovarian cancers. Yet, their role in ovarian tumor immunity remains poorly understood.

BH3 mimetics are apoptogenic but rarely cause immunogenic cell death (ICD), limiting durable antitumor immunity. We hypothesized that an ICD-inducing immunoadjuvant could convert BH3-mimetic-triggered tolerogenic apoptosis into immunogenic priming, enhancing checkpoint immunotherapy and overcoming immune evasion in AML. We in vivo evaluated the hydroxycoumarin OT-55, combined with the Bcl-xL inhibitor A-1331852, to enhance PD-1/Tim-3 blockade in Bcl-xL-dependent murine prophylactic and bilateral AML vaccination models. To define the clinical and immunological context, we derived a nine-gene AML ICD score (ATG5, CALR, CD8A, CD8B, IFNGR1, IL1B, PDIA3, PIK3CA, TLR4) by screening 34 ICD-associated genes in transcriptomes of three AML patient cohorts (TARGET-AML, BEAT-AML, GSE37642), retaining genes consistently associated with favorable prognosis (HR < 1, Cox regression). These cohorts were dichotomized by median ICD score to infer immune composition (CIBERSORTx) and profile driver mutations, and to assess blast maturation. High ICD scores were associated with an immune-activated state, increased CD8⁺ T cells, activated dendritic cells, and higher HAVCR2 (Tim-3) expression, consistent with a survival advantage. Bone marrow scRNA-seq from AML and healthy donors revealed ICD-related and progenitor-to-intermediate exhausted T cells, alongside T cell depletion in myelomonocytic AML. Experimentally, we used murine C1498 myelomonocytic AML cells to evaluate OT-55 combined with A-1331852 by prophylactic whole-cell vaccination for DAMP release, dependency testing (CRT neutralization and apyrase), antigen-specific CD8⁺ responses, and synergy with anti-PD-1/anti-Tim-3 therapy in a bilateral tumor model, while monitoring hematologic and serum parameters. OT-55 reduced C1498 viability, induced CRT exposure and ATP release, and conferred CRT/ATP-dependent, but HMGB1-independent, vaccine protection. While A-1331852 was cytotoxic yet weakly immunogenic, its combination with OT-55 enhanced DAMP release, increased CD8⁺ effector functions, and, with PD-1/Tim-3 blockade, achieved local and distant tumor control with low toxicity. These findings identify OT-55 as an immunogenic adjuvant converting tolerogenic BH3 mimetic-driven apoptosis into ICD, providing a proof-of-concept immunogenic treatment for myelomonocytic AML.

Reduced chloride channel accessory 4 (CLCA4) levels are linked to cancer development, while its role and mechanism in cancer stem cells (CSCs) remain unclear. In this study, we discovered that decreased CLCA4 expression was evident in CD133+CD44+ colorectal CSCs and chemoresistant colorectal cancer (CRC) cells. Increased expression of CLCA4 inhibited the expression of stemness genes, reduced tumorsphere formation, suppressed the self-renewal, migratory, and invasive capabilities of colorectal CSCs in vitro, and suppressed the tumorigenicity of colorectal CSCs in vivo. Mechanistically, CLCA4 interacted with vimentin, leading to FAK pathway inactivation and subsequent suppression of CSC expansion, while vimentin up-regulation attenuated the effects of CLCA4 down-regulation and established its role in CLCA4-mediated colorectal CSC self-renewal. Decreased CLCA4 expression was positively correlated with colorectal CSC markers and vimentin in clinical specimens. Increased CLCA4 expression promoted the infiltration of cytotoxic CD8+ T cells and enhanced the anti-PD-1 therapeutic efficacy. Our findings suggest that CLCA4 could impede colorectal CSC self-renewal by interacting with vimentin to suppress the FAK signaling pathway, potentially reducing tumor cell stemness and evading immune surveillance. The new findings on cellular and molecular mechanisms underpinning CRC development and progression could offer new perspectives for potential intervention and treatment of CRC.