PD-1 + CXCR5 − CD4 + Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma

作者：Jiangping Li, Changyou Wu, Ming‐Yuan Chen, Shangxin Liu, Shumei Yan, Yinfeng Kang, Cong Sun, Jennifer R. Grandis, Mu‐Sheng Zeng, Qian Zhong · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2021 · DOI：10.1136/jitc-2020-002101 · 被引用次数：97 · 研究领域：Cancer Immunotherapy and Biomarkers、Chemokine receptors and signaling、Immunotherapy and Immune Responses

Background A major current challenge is to exploit tertiary lymphoid structures (TLSs) to promote the lymphocyte infiltration, activation and differentiation by tumor antigens to increase antitumor immune responses. The mechanisms that underlie the role of TLS formation in the adaptive immune responses against nasopharyngeal carcinoma (NPC) remain largely unknown. Methods Cell populations and the corresponding markers were identified by single-cell RNA sequencing and fluorescence-activated cell sorting analysis. In vitro differentiation experiments were used to simulate the generation, regulation and function of the Th-CXCL13 cell subset in the tumor microenvironment of NPC. These were followed by histological evaluation of the colocalization of tumor-associated B cells (TABs) and Th-CXCL13 cells within TLSs, and statistical analysis of the relationship between the cells in TLSs and overall survival. Results A PD-1 + CXCR5 − CD4 + Th-CXCL13 cell subset was identified in NPC. This subset was a major source of CXCL13, representing the majority of the CD4 + T cells at levels comparable with Th1 and Tfh cells present in the TLSs. Monocytes activated by toll-like receptor 4 agonists served as the antigen-presenting cells that most efficiently triggered the expansion of Th-CXCL13 cells. Transforming growth factor beta 1 (TGF-β1) stimulation and activation of Sox4 were critical for the induction and polarization of Th-CXCL13 cells in this process. The potential functional contributi...