Cancer immunology research最新文献

Tumor-associated macrophages (TAM) play a crucial and important role in cancer dynamics by affecting homeostasis, immunosuppression, and angiogenesis within the tumor microenvironment. Using single-cell transcriptomics, we constructed a comprehensive atlas of myeloid cell populations across healthy and pan-cancer tissues that revealed heterogeneity. Our analysis suggested that TAMs may arise from two distinct origins: C1QC+ TAMs, which likely are derived from resident tissue macrophages, and SPP1+ TAMs and ISG15+ TAMs, which seem to originate from circulating monocytes. Regarding immature myeloid-derived suppressor cells (MDSC), we highlighted THBS1+ MDSCs and their descendants, SPP1+ TAMs, as key contributors to tumor progression, immunosuppression, and angiogenesis. We proposed a dichotomous model for TAMs, in which C1QC+ TAMs are associated with better patient outcomes, whereas the THBS1+ MDSC-SPP1+ TAM lineage correlates with poorer survival and unfavorable response to immunotherapy. This study offers insight into the complex interactions among monocyte-macrophage subtypes and sheds light on TAM heterogeneity and its implications for cancer progression and therapeutic strategies.

Large parallel genetic screens have been used to identify targets and regulators that enhance T-cell antitumor capability and persistence in the tumor microenvironment. We hypothesized that by combining the pooled screen data from multiple independent genetic screens, we could provide a systematic, comprehensive, and robust analysis of the effect of gene perturbation on T cell-based immunotherapies. After collecting data from previously published T-cell screens, including CRISPR-based and open reading frame-based screens, through the Gene Expression Omnibus, we reprocessed the gene hits summary and conducted a pathway enrichment analysis. A T-cell screen perturbation score metric was employed to quantify the impact of a gene perturbation on T-cell function. Additionally, gene expression data (both bulk RNA level and single-cell RNA level) from autoimmune disease cohorts and patients with T cell-derived cancer were incorporated to gain further insight into gene perturbations that potentially augment T-cell proliferation. We integrated all data and analysis on 35 T-cell screens into our state-of-the-art T-cell perturbation genomics database (TCPGdb), which is accessible through our web server (http://tcpgdb.sidichenlab.org/) and allows users to interactively explore the impact of query genes on T-cell function.

Patients with Sézary syndrome, the aggressive leukemic variant of cutaneous T-cell lymphoma, have few therapeutic options and a poor prognosis. We previously showed that the IL4/IL13 signaling pathway affects Sézary syndrome tumorigenesis. In this study, we investigated the potential therapeutic effect of REGN668 (dupilumab), an mAb that blocks the IL4/IL13 pathway by targeting the receptors' common IL4Rα subunit. We used single-cell RNA sequencing coupled with T-cell immune repertoire analysis to define the transcriptional changes and molecular mechanisms associated with REGN668 treatment in malignant and reactive T lymphocytes, as well as in monocytes and dendritic cells from the peripheral blood of patients with Sézary syndrome. Although REGN668 induced patient-specific transcriptional changes in malignant lymphocytes, it also downregulated several pro-tumorigenic processes that were shared across patient samples, including cell division, DNA damage/repair, autophagy, and T-cell signaling pathways. Ex vivo studies demonstrated that REGN668 inhibits proliferation of malignant lymphocytes more efficiently than blocking either IL4 or IL13 signaling alone. Furthermore, dupilumab reverts the immunosuppressive phenotype of non-clonal T lymphocytes and myeloid cells in the Sézary syndrome tumor microenvironment, including the function of myeloid-derived suppressor cells as well as Th2 and exhaustion pathways. Our study provides new insights into Sézary syndrome pathogenesis and a framework for precision therapies. Although case reports have raised concerns over dupilumab-induced cutaneous T-cell lymphoma, these seem attributable to initial misdiagnoses rather than a direct causative effect. Our findings indicate that dupilumab exerts pathway-specific effects and could contribute to a multi-pathway therapeutic approach.

Adoptive T-cell therapies have shown limited efficacy against solid tumors, so new approaches are required. In this issue, Chantzoura and colleagues describe MiNK-215, a novel allogeneic fibroblast activation protein-targeting chimeric antigen receptor invariant NK T-cell therapy engineered to secrete IL15. They show that it can remodel the tumor microenvironment and enhance antitumor immunity by depleting fibroblast activation protein-positive cancer-associated fibroblasts and activating multiple immune cell types. In mouse lung tumor and human organoid models, MiNK-215 promotes durable, antigen-specific T-cell responses and overcomes resistance to immunotherapy without causing off-target toxicity. See related article by Chantzoura et al., p. 243.

The activities of bispecific antibodies against VEGF and PD-1 have reinvigorated interest in dual VEGF and PD-1 targeting across solid tumors. However, the tumor and immune features influencing tumor response remain largely unknown. We conducted a single-arm phase II trial evaluating dual VEGFR2 and PD-1 targeting with ramucirumab and pembrolizumab in pretreated PD-L1+ gastric cancer. Twenty-six patients were enrolled between June 2021 and May 2023. Nine patients received anti-PD-1 therapy before trial enrollment. There were no complete responses, but six patients had a partial response, for an objective response rate of 23%. The median progression-free survival was 2.7 months, and the median overall survival was 10.9 months. Grade ≥3 treatment-related adverse events occurred in 39% of patients. Digital spatial profiling of serial primary tumor biopsies revealed distinct tumor microenvironment phenotypes between responders and nonresponders. Responders were characterized by higher baseline tumoral VEGF signaling, baseline enrichment in antigen processing and presentation in the immune compartment, shorter distances between tumor and immune cell populations, and greater on-treatment vascular normalization coupled to cytotoxic T-cell infiltration. Nonresponders had greater baseline hypoxia and platelet-derived growth factor scores, significantly upregulated TGFβ in immune cell regions, and greater distances between tumor and immune cells and immune cells and vessels. Paired peripheral blood mass cytometry revealed lower proportions of myeloid-derived suppressor cells in responders. Together, these data highlight on-treatment remodeling under the therapeutic pressure of dual VEGF and PD-1 blockade and suggest features associated with the durable benefit seen in a subset of patients.

Vaccines that encode tumor-associated antigens are potent boosting agents for adoptively transferred tumor-specific T cells. Employing vaccines to boost adoptively transferred tumor-reactive T cells relies on a priori knowledge of tumor epitopes, isolation of matched epitope-specific T cells, and personalized vaccines, all of which limit clinical feasibility. In this study, we investigated a universal strategy for boosting transferred tumor-specific T cells for which boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vaccine encoding the CAR target antigen. To this end, we developed and employed a model in which murine T cells expressing a T-cell receptor (TCR) specific for antigen on syngeneic tumors were engineered with boosting CARs against a distinct surrogate boosting antigen for studies in immunocompetent hosts. Boosting CAR-engineered tumor-specific T cells with paired vesicular stomatitis virus vaccines was associated with robust T-cell expansion and delayed tumor progression in the absence of prior lymphodepletion. CAR T-cell expansion and antitumor function were further enhanced by blocking IFNAR1. However, vaccine-boosted CAR T cells rapidly contracted and antigen-positive tumors re-emerged. In contrast, when the same T cells were boosted with a vaccine encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumor-specific endogenous cells expanded in parallel, and tumor cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated vaccine boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumor-reactive T cells during vaccination to achieve long-term tumor control.

The gut microbiome has emerged as a modulator of both cancer progression and patient responses to therapies like immune checkpoint inhibitors (ICI). Recent evidence highlights microbially derived metabolites as key regulators of immune response and tumor microenvironment dynamics. This review explores the role of four prominent classes of bacterial metabolites-inosine, indole, bile acids, and short-chain fatty acids-in shaping antitumor immunity and modulating ICI efficacy. Each of these metabolites and their derivatives demonstrate complex and context-dependent effects on immune cells. The duality of exerting both pro- and anti-inflammatory effects underscores the therapeutic potential and challenges of metabolite-targeted interventions. By examining current preclinical findings and ongoing clinical trials, we identify promising avenues for enhancing immunotherapy through microbiome modulation and call for further mechanistic insights to inform precision treatment strategies.

Invariant NK T (iNKT) cells are a conserved T-lymphocyte population capable of acting on dendritic cells (DC) to potently amplify downstream immune responses. However, the processes underlying such iNKT adjuvancy remain poorly understood. In this study, we showed that allogeneic human CD4+ iNKT cells form stably adhered bi-cellular complexes with monocyte-derived DCs that migrated together as pairs and showed extended DC calcium signaling. Compared with DCs treated with the synthetic adjuvant monophosphoryl lipid A, DCs complexed with iNKT cells had elevated expression of MHC class I and multiple costimulatory molecules, including 4-1BBL, OX40L, and IL15Rα, whereas the iNKT cells expressed CD70. Consistent with this distinctive costimulatory profile, iNKT-DC complexes were efficient activators of CD8+ T cells. Administering iNKT-DC complexes as a cellular immunotherapy in a xenograft model of aggressive human B-cell lymphoma resulted in rapid reduction in tumor mass, antigen-specific B-cell clearance, and transcriptional activation indicative of enhanced T-cell proliferation and effector responses. iNKT-DC immunotherapy was effective at late stages of tumor progression that were refractory to immune checkpoint blockade immunotherapy, suggesting that the consortium of activating signals provided by iNKT-DC complexes rejuvenates exhausted antitumor immunity. Finally, allogeneic CD4+ iNKT cells formed similar complexes with monocyte-derived DCs from patients with head and neck cancer and promoted tumor antigen-dependent CD8+ T-cell activation. These results show that monocyte-derived DCs paired with allogeneic CD4+ iNKT cells act as a potent antitumor cellular immunotherapy that activates antigen-specific CD8+ T-cell immunity.

The immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is predominantly shaped by tumor-associated macrophages (TAMs), yet the key chemokine axes driving immunosuppression and progression remain poorly defined. In this study, we identified the CCL1-AMFR axis as a critical contributor to GBM progression through dual immune-modulatory and tumor-intrinsic mechanisms. Analysis of human glioma datasets and tissue samples revealed that CCL1 - predominantly derived from TAMs - was significantly overexpressed in GBM and correlated with poor patient survival. Functionally, CCL1 recruited Arg1+ immunosuppressive macrophages in an AMFR-dependent manner. Myeloid-specific knockout of either Ccl1 or Amfr in murine models reduced TAM infiltration and extended survival. Although CCL1 can signal through both CCR8 and its recently identified receptor AMFR, AMFR played the dominant role in mediating CCL1-induced tumor cell proliferation and migration by activating the FAK and PI3K-AKT signaling pathways. Importantly, therapeutic neutralization of CCL1 using a monoclonal antibody significantly prolonged median survival in both immunocompetent GL261 murine GBM and BNI1-3 patient-derived xenograft (PDX) models, accompanied by reduced TAM infiltration and attenuated FAK/PI3K-AKT signaling. Our findings establish TAM-derived CCL1 as a pivotal regulator of GBM pathogenesis and demonstrate that targeting the CCL1-AMFR axis disrupts both tumor-intrinsic growth and immunosuppressive TME dynamics, representing a promising therapeutic strategy for this lethal malignancy.

Subcutaneous administration is an increasingly patient-preferred, alternative route of administration for monoclonal antibodies (mAb). To overcome the dose-volume restriction with subcutaneous administration and enable the large mAb doses typically required for immunotherapy, recombinant human hyaluronidase PH20 is co-dosed to transiently depolymerize hyaluronan at the injection site. Despite increasing clinical approvals and clinical trials of combination products with PH20, the potential impact of PH20 in facilitating intravenous-to-subcutaneous dose switching is largely unknown. In this study, we investigated whether increased lymphatic drainage via subcutaneous administration with PH20 co-dosing could improve the efficacy of anti-CTLA4 (αCTLA4) by increasing mAb access to the site of antitumor immunomodulation at the tumor-draining lymph node (TDLN). We showed that subcutaneous administration with PH20 significantly enhanced TDLN exposure of αCTLA4. In murine tumor models (CT26/HAS or MC38/OVA), this translated to improved tumor control compared with intravenous, and was either more efficacious or noninferior to subcutaneous alone. Greater efficacy occurred concomitantly with increased cytotoxic effector CD8+ T cells in the tumor and CD62L+ stem-like CD8+ T cells in the TDLN. This was due to increased mAb access to CTLA4+ T-cell populations at the TDLN and was only preserved at a lower mAb dose after subcutaneous administration with PH20. The efficacy advantage of subcutaneous administration with PH20 was primarily apparent for TDLN-targeted mAb (αCTLA4), as combination therapy with a non-TDLN-targeted mAb (αTIM3) was similarly efficacious regardless of dose routes. Overall, our study highlights the potential utility of PH20 to improve TDLN-targeted immunotherapy.