Cancer immunology research最新文献

Targeted therapies for NRAS-mutant melanoma remain an unmet clinical need. In this study, we demonstrate that RMC-7977, a preclinical RAS(ON) multiselective 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 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 patients with NRAS-mutant melanoma treated with daraxonrasib in an ongoing phase I/Ib clinical trial. Together, these data support the continued clinical evaluation of RAS(ON) multiselective inhibitors for the treatment of NRAS-mutant melanoma.

Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective. However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. In this study, using joint single-cell transcriptome and T-cell receptor profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node (LN) in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes upregulated gene signatures of T-cell activation and exhaustion compared with those recognizing other tumor antigens. In the tumor-draining LN, we identified TCF1+TOX- stem cell memory T cells (TSCM), TCF1+TOX+ progenitor exhausted T cells (TPEX), and TCF1-TOX+ effector-like exhausted CD8+ T cells (TEX) subsets among neoantigen-specific CD8+ T cells. Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared with clones biased toward TEX, TPEX, or TSCM. The TPEX subset had the greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point in which neoantigen-specific clones exited the LN and differentiated into TEX tumor-infiltrating lymphocytes. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the LN negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph node residence predicted a poorer response to immune checkpoint inhibitors by patients with cancer. In conclusion, we have identified a transcriptional program that controls the cell fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in patients with cancer.

The immune microenvironment is a crucial component of colorectal carcinoma that has been well characterized, but much less is known about the immune microenvironment of colorectal carcinoma 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 colorectal carcinoma precursors (including hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, tubular adenomas, tubulovillous adenomas, and villous adenomas) and 1,035 colorectal carcinomas. We performed an in situ multispectral immunofluorescence assay for CD3, CD4, CD8, FOXP3 (negative, low, or high expression), PTPRC (CD45RO and CD45RA), MKI67 (Ki-67), and KRT (keratin) 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 with other precursors and carcinomas. Age strata of patients with precursors (including early-onset precursors) were not associated with differential T-cell infiltration patterns. Compared with invasive colorectal carcinoma, 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 histopathologic 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 colorectal carcinoma.

Tumor-specific CD8+ T cells in blood seem to be important for and predictive of response to anti-PD-1 therapies. However, as most tumor antigens are unique to a given patient, the identification of tumor-specific CD8+ T cells is not routinely feasible. In this study, we characterized polyomavirus-specific CD8+ T cells from the blood of 17 patients with virus-driven Merkel cell carcinoma. We identified a 98-gene signature [Signature of Peripheral Tumor-specific CD8+ T cells (SPoTT)] that discriminated circulating tumor-specific CD8+ T cells from other T cells in immunotherapy-naïve patients. We observed profound transcriptomic differences among tumor-specific CD8+ T cells from blood versus those from tumor. In validation cohorts of Merkel cell carcinoma, as well as neoantigen-driven cancers, the signature of peripheral tumor-specific CD8+ T cells was able to identify viral oncoprotein- and neoantigen-specific CD8+ T cells with both sensitivity and specificity above 75%. We also tested a previously described 151-gene signature (NeoTCRPBL) trained on neoantigen-specific CD8+ T cells and found it was able to recognize Merkel cell polyomavirus-specific T cells with a sensitivity of 66% and a specificity of 88%. These findings show that circulating tumor-specific CD8+ T cells share fundamental characteristics across diverse tumor antigen types. More broadly, insights into antitumor T cells gained from virus-driven cancers are also likely to be relevant in mutationally driven cancers.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of cancer. However, the durable response to this therapy remains low, and there is a risk of moderate-to-severe toxicities following treatment that requires close monitoring. Over the past decade, we have learned that cytokines play an important role in mediating CAR T cell-associated toxicities and efficacy. As such, cytokine modulation has become a popular area of investigation to improve therapeutic responses. Although the relationship of many cytokines with CAR T-cell therapy has been investigated, several recent studies suggest paradoxical roles for cytokines such as IFNγ, IL2, IL4, and IL10 in CAR T-cell response and toxicity. In this review, we summarize the history of these cytokines in immunotherapies, detail the contexts in which these cytokines have been beneficial or harmful in the context of CAR T-cell therapy, and discuss factors that may be dictating their pleiotropy.

Human leukocyte antigen class I (HLA-I) is central to tumor immune recognition, but its regulatory mechanisms in cervical cancer remain poorly understood. This study aimed to elucidate the impact of HLA-I regulatory mechanisms on CD8+ T-cell infiltration and identify distinct histotype-specific immune escape strategies across cervical cancer subtypes. Using 98 cervical cancer cases, including squamous cell carcinoma (SCC; n = 53), adenocarcinoma (n = 32), gastric-type adenocarcinoma (GAS; n = 5), small cell carcinoma (Small, n = 4), and mixed histologic types (n = 4), we examined the relationship between CD8+ T-cell infiltration patterns (categorized as infiltrated, excluded, or absent) and HLA-I expression, HLA-A DNA methylation, and HLA-I loss of heterozygosity (LOH). CD8+ T-cell infiltration patterns varied significantly by histologic subtype (P < 0.0001). SCC showed the highest frequency of the infiltrated pattern (73.6%), whereas GAS and Small predominantly displayed an absent pattern. Reduced CD8+ T-cell infiltration correlated with poor survival (P < 0.0001). HLA-I expression mirrored these trends being highest in SCC and lowest in Small and GAS. HLA-A DNA methylation emerged as a key driver of HLA-I downregulation, leading to reduced CD8+ infiltration (P < 0.05). In SCC, both HLA-A methylation and HLA-I LOH contributed to immune evasion; cases lacking these alterations exhibited the highest CD8+ T-cell infiltration levels (P < 0.01). This study identifies distinct HLA-I regulatory mechanisms in cervical cancer, highlighting HLA-A methylation-and particularly HLA-I LOH in SCC-as key drivers of immune evasion. These findings provide a foundation for developing predictive biomarkers and suggest that targeting these specific HLA-I regulatory mechanisms could enhance immunotherapy efficacy.

NK cells play a critical role in anticancer immunity through their direct cytotoxicity and production of cytokines, such as FMS-like tyrosine kinase 3 ligand (Flt3L). NK cell production of Flt3L controls conventional type I dendritic cell (cDC1) abundance in the tumor and promotes protective immune responses. In this study, we show that NK cell production of Flt3l in the tumor is regulated by activation and that activation by IL2 and IL15 uniquely induced Flt3L expression in NK cells. In melanoma, IL2 signaling in NK cells led to increased Flt3L production, which boosted cDC1 abundance in the tumor and improved anti-PD-1 immunotherapy response. Furthermore, NK cell subsets differentially regulated Flt3l in the tumor, with CD11b-CD27+ NK cells in mouse tumors enriched for IL2 family signaling and upregulating Flt3l upon activation. Consistently, human CD56brightCD16- NK cells more strongly correlated with cDC1 and FLT3LG expression than other NK cell subsets across multiple human melanoma datasets and cancer indications. This mechanistic study of NK cell regulation of FLT3LG and control of the NK cell-cDC1 axis provides insights and strategies for the development of more effective cancer immunotherapies.

Immune checkpoint blockade (ICB) has transformed colorectal cancer therapy, yet the majority of microsatellite-stable colorectal cancers remain refractory because of insufficient tumor-immune cell cross-talk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. In this study, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in colorectal cancer, as a key driver of immune evasion. Despite low cytotoxicity to normal cells, HNRNPA2B1 rewired the TIME by suppressing Cxcl9/Cxcl10-Cxcr3 signaling, CD8+ T-cell infiltration, and MHC class I antigen presentation, resulting in a noninflamed ("cold") tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell-mediated tumor clearance, and sensitized microsatellite-stable colorectal cancers to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1's impact on tumor-immune interactions, and it strongly correlated with immune infiltration, epithelial-mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in colorectal cancer.