Expansion of CD4+ cytotoxic T lymphocytes with specific gene expression patterns may contribute to suppression of tumor immunity in oral squamous cell carcinoma: single-cell analysis and in vitro experiments

细胞毒性T细胞 生物 CD8型 癌症研究 免疫学 T细胞 免疫疗法 白细胞介素21 颗粒酶 免疫系统 体外 穿孔素 生物化学
作者
Chen Hu,Junsei Sameshima,Shiho Yokomizo,Tomoki Sueyoshi,Haruki Nagano,Yuka Miyahara,Taiki Sakamoto,Shinsuke Fujii,Tamotsu Kiyoshima,Thomas Guy,Seiji Nakamura,Masafumi Moriyama,Naoki Kaneko,Shintaro Kawano
出处
期刊:Frontiers in Immunology [Frontiers Media]
卷期号:14 被引量:4
标识
DOI:10.3389/fimmu.2023.1305783
摘要

Background 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. Methods 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. Results 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. Conclusion 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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