Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Cancer Immunol Res. 2019 May;7(5):784-796. doi: 10.1158/2326-6066.CIR-18-0517. Epub 2019 Mar 14.
The chemokine CXCL13 mediates recruitment of B cells to tumors and is essential for the formation of tertiary lymphoid structures (TLSs). TLSs are thought to support antitumor immunity and are associated with improved prognosis. However, it remains unknown whether TLSs are formed in response to the general inflammatory character of the tumor microenvironment, or rather, are induced by (neo)antigen-specific adaptive immunity. We here report on the finding that the TGFβ-dependent CD103CD8 tumor-infiltrating T-cell (TIL) subpopulation expressed and produced CXCL13. Accordingly, CD8 T cells from peripheral blood activated in the presence of TGFβ upregulated CD103 and secreted CXCL13. Conversely, inhibition of TGFβ receptor signaling abrogated CXCL13 production. CXCL13CD103CD8 TILs correlated with B-cell recruitment, TLSs, and neoantigen burden in six cohorts of human tumors. Altogether, our findings indicated that TGFβ plays a noncanonical role in coordinating immune responses against human tumors and suggest a potential role for CXCL13CD103CD8 TILs in mediating B-cell recruitment and TLS formation in human tumors.
趋化因子 CXCL13 介导 B 细胞向肿瘤募集，是形成三级淋巴结构 (TLS) 的必要条件。TLS 被认为支持抗肿瘤免疫，并与改善的预后相关。然而，尚不清楚 TLS 是否是对肿瘤微环境的一般炎症特征的反应形成的，还是由（新）抗原特异性适应性免疫诱导的。我们在这里报告的发现是，依赖 TGFβ 的 CD103CD8 肿瘤浸润性 T 细胞 (TIL) 亚群表达并产生 CXCL13。相应地，在 TGFβ 存在下激活的外周血 CD8 T 细胞上调 CD103 并分泌 CXCL13。相反，抑制 TGFβ 受体信号会消除 CXCL13 的产生。CXCL13CD103CD8 TIL 与六个人类肿瘤队列中的 B 细胞募集、TLS 和新抗原负担相关。总之，我们的研究结果表明，TGFβ 在协调针对人类肿瘤的免疫反应中发挥非典型作用，并表明 CXCL13CD103CD8 TIL 在介导人类肿瘤中的 B 细胞募集和 TLS 形成中具有潜在作用。
