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Human CD4 cytotoxic T lymphocytes mediate potent tumor control via tumor cell HLA 2 class II expression in a humanized immune system mouse model

ABSTRACT: Efficacy of immune checkpoint inhibitors in cancer can be limited by dysfunction of CD8 T cells or down-regulation of HLA class I. Tumor control mechanisms independent of the CD8/HLA-I axis would bypass these limitations. CD4 cytotoxic T lymphocytes (CTLs) have been detected in diverse human cancers. However, their independent roles in tumor immunity are underexplored. Here, we report CD4 T cell-dependent spontaneous tumor regression and subsequent memory responses in a humanized immune system (HIS) mouse model. HT-29 tumors, which upregulate HLA class II expression in response to IFN-γ, regressed or were eliminated in a subset of tumor implanted HIS mice. Mice with regressing tumors showed increased cytotoxic CD4 T cells in blood and tumors and enhanced HLA-II expression on tumor cells compared to mice with progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor cell-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating potent tumor control independent of CD8 T cells and provides a novel platform to study human CD4 CTL-mediated anti-tumor immunity.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE223026 | GEO | 2023/01/22

REPOSITORIES: GEO

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Project description:Cancer immunotherapy targeting CD8+ T cells has made remarkable progress, even for oral squamous cell carcinoma (OSCC), a heterogeneous epithelial tumor without a substantial increase in the overall survival rate over the past decade. However, the therapeutic effects remain limited due to therapy resistance. Thus, a more comprehensive understanding of the roles of CD4+ T cells and B cells is crucial for more robust development of cancer immunotherapy. In this study, we examined immune responses and effector functions of CD4+ T cells, CD8+ T cells and B cells infiltrating in OSCC lesions using single-cell RNA sequencing analysis, T cell receptor (TCR) and B cell receptor (BCR) repertoire sequencing analysis, and multi-color immunofluorescence staining. Finally, two Kaplan-Meier curves and several Cox proportional hazards models were constructed for the survival analysis. We observed expansion of CD4+ cytotoxic T lymphocytes (CTLs) expressing granzymes, which are reported to induce cell apoptosis, with a unique gene expression patterns. CD4+ CTLs also expressed CXCL13, which is a B cell chemoattractant. Cell-cell communication analysis and multi-color immunofluorescence staining demonstrated potential interactions between CD4+ CTLs and B cells, particularly IgD- CD27- double negative (DN) B cells. Expansion of CD4+ CTLs, DN B cells, and their contacts has been reported in T and B cell-activated diseases, including IgG4-related disease and COVID-19. Notably, we observed upregulation of several inhibitory receptor genes including CTLA-4 in CD4+ CTLs, which possibly dampened T and B cell activity. We next demonstrated comprehensive delineation of the potential for CD8+ T cell differentiation towards dysfunctional states. Furthermore, prognostic analysis revealed unfavorable outcomes of patients with a high proportion of CD4+ CTLs in OSCC lesions. Our study provides a dynamic landscape of lymphocytes and demonstrates a systemic investigation of CD4+ CTL effects infiltrating into OSCC lesions, which may share some pathogenesis reported in severe T and B cell-activated diseases such as autoimmune and infectious diseases.

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Human CD4 cytotoxic T lymphocytes mediate potent tumor control via tumor cell HLA 2 class II expression in a humanized immune system mouse model

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