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A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability–high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability–high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A , converged on reduced expression of HLA-ABC genes. Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy. [Display omitted] Mutational analysis of HLA-ABC genes using a long-read sequencer revealed the mechanistic bases of immune evasion and identified several gene mutations that contribute to immune evasion. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13 , highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (T FH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the T FH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. T FH -like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic T FH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into T FH -like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells. [Display omitted] • CXCL13 produced by exhausted CD8+ T cells in the TME recruits T FH cells • A part of T FH cells has cytotoxicity against MHC-II-expressing tumors • The BLIMP1/TCF1 axis determines the differentiation of cytotoxicity • T FH -like CD4+ T cells in the TME have features similar to exhausted CD8+ T cells Zhou et al. demonstrate that CXCL13 produced by cancer-specific exhausted CD8+ T cells in the TME recruits T FH cells, a part of which exhibits cytotoxicity. The BLIMP1/TCF1 axis determines the nature of these T FH cells, which resembles the concept of stem-like progenitor/terminally differentiated exhaustion in CD8+ T cells. [ABSTRACT FROM AUTHOR]

The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression. [Display omitted] • LA induces PD-1 expression by Treg cells in highly glycolytic tumors • LA absorbed through MCT1 is a metabolic checkpoint of immune responses • MYC -amplified or liver metastatic tumors augment PD-1+ Treg cells with abundant LA • MCT1 highly expressed by Treg cells provides therapeutic target for immunotherapy Kumagai et al. show that Treg cells uptake lactic acid in the highly glycolytic tumor microenvironment via MCT1 and robustly express PD-1, resulting in the impairment of PD-1 blockade therapy. [ABSTRACT FROM AUTHOR]