Cancer immunology research最新文献

Large parallel genetic screens have been used to identified targets and regulators that enhance T cell antitumor capability and persistence in 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 ORF-based screens, through Gene Expression Omnibus (GEO), we reprocessed the gene hits summary and conducted a pathway enrichment analysis. A T cell screen perturbation score (TPS) 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 cohort and T cell-derived cancer patients were incorporated to gain further insight on gene perturbations that potentially augment T cell proliferation. We integrated all data and analysis on 35 T cells screens into our state-of-the-art T cell perturbation genomics database (TCPGdb), which is accessible through our webserver (http://tcpgdb.sidichenlab.org/) and allows users to interactively explore the impact of query genes on T cell function.

The activity of bispecific antibodies against vascular endothelial growth factor (VEGF) and programmed death ligand-1 (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 pre-treated 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%. Median progression-free survival was 2.7 months, and 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 non-responders. 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. Non-responders had greater baseline hypoxia and PDGF scores, significantly upregulated TGF-β 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.

Cellular immunotherapies show remarkable efficacy against hematological malignancies. However, applying these therapies against solid tumors is challenging. Among the obstacles are the lack of tumor-specific antigens and the immunosuppressive tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein (FAP) are key contributors in shaping this immunosuppressive landscape, yet developing effective strategies for targeting these cells remains an ongoing challenge. Here, we describe the design, generation, and characterization of MiNK-215, an allogeneic human invariant natural killer T (iNKT) cell therapy in which iNKT cells were engineered to express a FAP-targeting chimeric antigen receptor (CAR) and to secrete interleukin-15 (IL-15) to remodel the TME and enhance antitumor activity. MiNK-215 modulated multifunctional immune responses by enhancing T-cell responsiveness, dendritic-cell activation, M1 macrophage polarization, and tumor killing. In a lung tumor mouse model, MiNK-215 depleted FAP+ CAFs, enhanced antigen-specific T-cell infiltration, and promoted durable antitumor immunity without off-target toxicity. These findings were extended to human organoid models of treatment-refractory Microsatellite Stable Colorectal Cancer (MSS-CRC) liver metastases, establishing FAP-CAR-IL-15 iNKT cells as a promising strategy to overcome immunotherapy resistance in solid tumors.

Invariant Natural Killer T (iNKT) cells are a conserved T lymphocyte population capable of acting on dendritic cells (DCs) to potently amplify downstream immune responses. However, the processes underlying such iNKT adjuvancy remain poorly understood. Here, 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 to DCs treated with the synthetic adjuvant monophosphoryl lipid A (MPLA), DCs complexed with iNKT cells had elevated expression of MHC class I and multiple costimulatory molecules including 4-1BBL, OX40L, and IL-15R, while the iNKT cells expressed CD70. Consistent with this distinctive co-stimulatory 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 Head and Neck Cancer patients 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.

Tumor-associated macrophages (TAMs) play 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, SPP1+ TAMs and ISG15+ TAMs, which appear to originate from circulating monocytes. Regarding immature myeloid-derived suppressor cells (MDSCs), 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+ MDSCs - SPP1+ TAMs 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.

The immune microenvironment is a crucial component of colorectal carcinoma (CRC) that has been well characterized, but much less is known about the immune microenvironment of CRC precursors. We hypothesized that T-cell infiltrates might differ across the colorectal neoplastic spectrum. We leveraged the prospective cohort incident-tumor biobank method, which provided formalin-fixed paraffin-embedded tumor tissue specimens (N=1,825) from 790 CRC precursors (including hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, tubular adenomas, tubulovillous adenomas, and villous adenomas) and 1,035 CRCs. We performed an in situ multispectral immunofluorescence assay for CD3, CD4, CD8, FOXP3 (negative, low, or high expression), PTPRC (CD45RO, CD45RA), MKI67 (Ki-67), and KRT combined with supervised machine learning. CD3+CD4+ cells were more abundant than CD3+CD8+ cells in most precursors. In conventional adenomas, greater villous component correlated with fewer intraepithelial CD3+CD8+ cells. Serrated lesions, including hyperplastic polyps and sessile serrated lesions, exhibited higher densities of intraepithelial CD3+CD8+ cells compared to other precursors and carcinomas. Age strata of patients with precursors (including early-onset precursors) were not associated with differential T-cell infiltration patterns. Compared to invasive CRC, precursors generally showed higher densities of CD3+CD4+ cells and CD3+CD8+ cells with phenotypes of naive (CD45RA+CD45RO-), memory (CD45RA-CD45RO+), and regulatory (FOXP3+Low and FOXP3+High) in intraepithelial and lamina propria/stromal regions. In conclusion, T-cell infiltration patterns vary across different histopathological types of the colorectal neoplastic spectrum from precursors to invasive carcinomas. Our findings shed light on how the tumor-immune microenvironment evolves during precursor development and progression to CRC.

Despite advances in immune checkpoint blockade (ICB) for cancer treatment, only a minority of triple-negative breast cancer (TNBC) patients derive benefits, and the underlying mechanisms remain largely unknown. Herein, sequence similarity 135 family member B (FAM135B) is identified as a regulator of antitumor immunity in TNBC. Single-cell sequencing data and functional assays demonstrate the critical role of FAM135B in activating cytotoxic T cells and improving the efficacy of ICB treatment by stimulating the STING pathway. Specifically, FAM135B interacts with IFI16, inhibiting its ubiquitination and proteasomal degradation by competitively blocking its binding to the E3 ligase TRIM21, thereby initiating the IFI16-dependent STING signaling, ultimately leading to increased cytotoxic T cell activity. The deubiquitination of IFI16 at lysine 143 and lysine 561 is crucial for FAM135B-mediated activation of the STING pathway. These findings reveal that FAM135B regulates the IFI16-dependent STING pathway and subsequent immune activation. FAM135B may represent a potential predictor of ICB therapeutic responses for TNBC patients.

Effective antitumor immunity ultimately depends on the priming and activation of tumor-specific cytotoxic CD8+ T cells; however, the role of intratumoral cell-cell immune interactions remains incompletely understood. Recent work has revealed that the temporospatial colocalization of dendritic cells (DCs), helper T cells (Th), and cytotoxic T lymphocytes (CTL) within the tumor immune microenvironment following immune checkpoint blockade correlates with clinical response. Herein, we report the integration of more than one million spatially resolved single-cell profiles across six spatial proteomic and transcriptomic assays, which demonstrated that DC:Th:CTL three-cell-type clusters were common even in immunotherapy-naïve and highly desmoplastic tumors, such as fibrolamellar carcinoma and pancreatic ductal adenocarcinoma (PDAC). We found that these immune triads were enriched for functionally important type 1 conventional DC, mature DCs enriched in immunoregulatory molecules (mregDC), CXCL13+ Th, and GZMK+ effector CTL phenotypes. Subsequent multiplex immunofluorescence imaging of more than 450 primary PDAC tumors showed that the density of antigen-presenting cell (APC):Th:CTL three-cell-type clusters was correlated with intratumoral T-cell clonal expansion and improved overall survival. These findings suggest that DC:Th:CTL triads are conserved across solid tumors and highlight the importance of intratumoral spatial niches in mediating endogenous antitumor immunity.

Targeted therapies for NRAS-mutant melanoma remain an unmet clinical need. Here, we demonstrate that RMC-7977, a preclinical RAS(ON) multi-selective inhibitor representative of the investigational agent daraxonrasib (RMC-6236), was able to elicit potent antitumor immune responses across multiple NRAS-mutant melanoma models. Treatment with RMC-7977 led to rapid tumor regressions driven by inhibition of MAPK signaling, upregulation of major histocompatibility complex (MHC) and PD-L1 proteins, and enhanced infiltration of CD4⁺ and CD8⁺ T cells. Complete responses were dependent on adaptive immunity, as both CD4⁺ and CD8⁺ T cells were essential for extended survival. Resistance to treatment was marked by reduced T-cell infiltration, loss of MHC class I expression, and expansion of myeloid-derived suppressor cells. Combining RMC-7977 with anti-PD-1 boosted cytotoxic T-cell infiltration, reprogrammed myeloid cells toward an antigen-presenting phenotype, and improved survival in models resistant to PD-1 blockade. Consistent with these preclinical data, objective clinical responses were observed in two NRAS-mutant melanoma patients treated with daraxonrasib in an ongoing Phase I/Ib clinical trial. Together, these data support the continued clinical evaluation of RAS(ON) multi-selective inhibitors for the treatment of NRAS-mutant melanoma.