Oncoimmunology最新文献

The recent FDA approval of lurbinectedin plus atezolizumab for advanced small cell lung cancer underscores the promise of combining immunogenic cell death (ICD) inducers with PD-1/PD-L1 blockade. This synergistic strategy induces durable responses in refractory tumors and may extend immunotherapy benefits across diverse malignancies through rational ICD-checkpoint inhibitor combinations.

CD91 serves as a receptor that causes the activation of antigen-presenting cells in response to cancer cells by binding HSPs. In this context, the HSP-CD91 axis is responsible for the rejection of emerging and nascent cancers. The role of CD91 in the cross-presentation of HSP-chaperoned peptides is well established, but its contribution to cell signaling and costimulation is less clear. We investigated CD91-mediated signaling with respect to cancer immunosurveillance by examining two key adaptor proteins, Fgr and AXL. To investigate the interactions between the β chain of CD91 and Fgr and AXL, AlphaFold was used to predict protein‒protein binding areas. Signaling was further investigated by examining NF-κB phosphorylation and cytokine production in iBMDMs with CRISPR-induced tyrosine mutations. Mice conditionally lacking Fgr and AXL in dendritic cells were assessed for their ability to control tumors in inducible and transplantable models of cancer. In silico or CRISPR-mediated disruption of key tyrosines within CD91 abrogates Fgr binding, NF-κB activation, and cytokine release. Using a DC-specific Fgr knockout mouse model, we revealed that loss of Fgr severely impaired tumor immunosurveillance, whereas AXL knockout resulted in a milder phenotype, suggesting a greater downstream role. Loss of Fgr also prevents the development of adaptive immunity to tumors following HSP immunization, but it has no impact on transplantable tumor growth. These findings elucidate key components of the CD91 signaling mechanism, advancing our understanding of how dying tumor cells initiate adaptive immune responses and providing a therapeutic target to enhance this pathway.

While recent advances in immuno-oncology have revolutionized cancer therapy, only a subset patients benefit from these treatments and achieve durable clinical responses. Biomarker-guided identification of patients likely to respond to immunotherapy could enable more effective management of various malignancies. To explore this, we took advantage of a Phase I trial evaluating the efficacy of antigen-engineered dendritic cell (DC) vaccine, administered either as monotherapy or in combination with high-dose interferon-α2b, in promoting anti-tumor immunity in melanoma patients. Liquid biopsies, including serum and peripheral blood mononuclear cells, and tumor biopsies were previously analyzed for predictive markers using Luminex, NanoString gene expression profiling and flow cytometry. Here, in vitro stimulation assays were conducted to assess arginase-1 production by circulating myeloid subsets. Of 73 serum analytes, serum arginase-1 (sArg1) most effectively distinguished melanoma patients with measurable disease from healthy donors. Elevated sArg1 levels in patients with active disease correlated with favorable responses to the vaccine and were associated with longer overall and progression-free survival. Integrated phenotypic, functional and metabolic analyses identified circulating CD14^-CD11c⁺ DC3 as the likely source of sArg1. These findings support the hypothesis that sArg1 may serve as a biomarker for responsiveness to cancer vaccine immunotherapy and reflect systemic myeloid cell fitness associated with enhanced anti-tumor immunity. Given the stability and accessibility of serum compared to cells or tissues, this assay could offer a method for assessing patient status, potentially improving stratification and clinical decision-making.

Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.

We conducted a phase Ib/II clinical trial to evaluate the safety, feasibility, and clinical activity of combining pembrolizumab (anti-PD-1) with XL888 (Hsp90 inhibitor) in patients with advanced colorectal cancer (CRC). We hypothesized that this regimen would modulate soluble and cellular immune mediators and enhance clinical outcomes. The trial employed a 3 + 3 open-label design, with an expansion cohort at the recommended phase II dose (RP2D) in treatment-refractory, mismatch repair-proficient CRC patients. Comprehensive analyses of plasma cytokines, peripheral blood mononuclear cells (PBMCs), and spatial immune cell patterns in liver biopsies were performed to identify unique immune signatures resulting from the combined therapy. The combination of pembrolizumab and XL888 proved to be safe and feasible, with a subset of patients achieving stable disease, although no objective responses were observed in this heavily pre-treated population. Correlative studies revealed immunomodulatory effects in tumors and circulation, including a reduction in IL6⁺ cells and macrophages (CD68⁺) within metastatic liver tissue, alterations in blood CD3⁺ cells, and upregulation of numerous inflammatory plasma cytokines. These findings suggest local and systemic immune activation by the combination of pembrolizumab and XL888. While clinical activity was modest in treatment-refractory CRC patients, there were notable effects on the tumor immune environment and systemic immune modulation.

Regulatory T cells (Tregs) contribute significantly to the immunosuppressive nature of the tumor microenvironment which is a main barrier for immunotherapies of solid cancers. Reducing Treg numbers enhances anti-tumor immune responses but current depletion strategies also impair effector T cells (Teffs), potentially leading to reduced anti-tumor immunity and/or autoimmune diseases. CD137 has been identified as the most differentially expressed gene between peripheral Tregs and intratumoral Tregs in virtually all solid cancers. Further, CD137 is expressed by malignant cells of certain cancers, making it a potential target for tumor immunotherapy. Here, we report the development of a fully human anti-human CD137 antibody of the IgG1 isotype, clone P1A1, that induces antibody-dependent cell-mediated cytotoxicity (ADCC) in CD137⁺ Tregs and cancer cells. P1A1 cross-reacts with murine CD137 which allowed testing murine chimeric P1A1 in syngeneic murine tumor models where P1A1 significantly reduced the number of CD137⁺ Tregs and inhibited tumor growth in a murine hepatocellular carcinoma (HCC) and a melanoma lung metastasis model. P1A1 can also be internalized thus enabling it as a carrier for drugs to target CD137⁺ Tregs and cancer cells. These anti-cancer properties suggest a translation of P1A1 to human immunotherapy.

Nivolumab plus ipilimumab (aCTLA-4/aPD-1) combination therapy has significantly improved clinical outcomes in patients with metastatic melanoma, with 50%-60% of patients responding to treatment, but predictors of response are poorly characterized. We hypothesized that circulating cytokines and peripheral white blood cells may predict response to therapy and evaluated 15 cytokines and complete blood counts (CBC with differentials) from 89 patients with advanced melanoma treated with combination therapy from three points in time: pre-treatment, one month and approximately three months after starting therapy. Clinical endpoints evaluated included durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS). A parsimonious predictive model was developed to identify cytokines predictors of response to combination therapy. In this study, we found that pre-treatment, patients with DCB had higher IL-23, lower CXCL6, and lower IL-10 levels. Lower NLR one month after starting therapy predicted better PFS and OS, primarily driven by an increase in absolute lymphocytes. A multivariate model demonstrated that baseline CXCL6, IL-10, IL-23 were independent predictors of therapy response, and the combined model has reached an area under the curve (AUC) of 0.79 in prediction of response to combination therapy. Our study identified baseline CXCL6, IL-23, and IL-10 as predictors of response to aCTLA4/aPD1 combination therapy among patients with metastatic melanoma. This study also provides a framework for identifying patients who are likely to respond to combination ICB, as well as a subset of patients with high risk of developing resistance and are thus in need of alternative therapeutic options, such as clinical trials.

Nonmutated mitochondrial DNA (mtDNA) from T lymphocytes can be incorporated into cancer cells bearing mutated mtDNA to repair their bioenergetic deficiency. However, a recent paper by Ikeda et al. indicates that mutated mtDNA from malignant cells can also be transferred into tumor-infiltrating T lymphocytes to subvert their function in cancer immunosurveillance.

Glioblastoma (GB) remains refractory to chimeric antigen receptor (CAR)-T cell therapy, mainly attributed to tumor heterogeneity and antigen escape. CAR-T cells utilizing monomeric streptavidin-2 (mSA2) instead of a traditional target binding domain, bind biotinylated antibodies and can be directed to variable targets to mediate anti-tumor effects. Although such an approach might circumvent the aforementioned challenges, the potential of mSA2 CAR-T cells for brain tumor treatment remains unexplored. In this study, we generated mSA2 CAR-T cells and tested their efficacy against GB by tailoring their specificity toward GB-associated markers CD276, EPHA2, CD70 and IL13Ra2. In vitro, mSA2 CAR-T cells specifically recognized multiple primary GB cell lines in a target- and biotinylated antibody-dependent manner. Moreover, in heterogenous tumor environments, mSA2 CAR-T cells simultaneously targeted multiple subpopulations, guided by combinations of biotinylated antibodies, indicating their potential to address tumor heterogeneity. Finally, the mSA2 CAR-T cell-mediated anti-tumor functions were demonstrated in vivo. Immunocompromised mice orthotopically implanted with CD70⁺ or CD276⁺ GB cells and treated with mSA2 CAR-T cells pre-armed with antibodies against these two antigens exhibited control of tumor growth and induction of GB cell apoptosis after therapy. Taken together, our study suggests that antibody-guided mSA2 CAR-T cells can target potentially any surface GB-related antigen both in vitro and in vivo, either univalently or multivalently, with underlined clinical implications.

In most cancers, T lymphocytes comprise an essential cellular component of the non-neoplastic microenvironment, where they have the capacity to both suppress and support tumor growth. One specialized T lymphocyte population is the CD8⁺ exhausted T cell, which has been intensely studied as an actionable therapeutic target. Unfortunately, there is currently no uniformly accepted classification scheme for these specialized T cells. To provide a potential model for classifying CD8⁺ exhausted T cells, we leveraged single cell transcriptomic analysis of a diverse collection of both human (n = 8) and mouse (n = 4) cancers to identify unique subpopulations shared across tumor types and species. By integrating data from both human and mouse cancer studies, as well as previously described CD8⁺ exhausted T cell subsets, we provide an integrated framework to characterize the heterogeneity of exhausted CD8⁺ T cells. As such, one of these subpopulations (cluster C1) increases following immune checkpoint inhibitor treatment in the setting of cancer in mice and patients. Taken together, this proposed classification scheme may be useful for the design and interpretation of current and future immune-based therapy studies.