| Summary: | The chemokine CXCL13 mediates recruitment of B cells to tumors and is essential for the formation of tertiary lymphoid structures (TLS). TLS are thought to support antitumor immunity and are associated with improved prognosis. However, it remains unknown whether TLS are formed in response to the general inflammatory character of the tumor micro-environment, or rather, are induced by (neo-)antigen-specific adaptive immunity. We here report on the unexpected finding that the transforming growth factor beta (TGF-β)-dependent CD103+ CD8+ tumor-infiltrating T cell (TIL) subpopulation expressed and produced CXCL13. Accordingly, CD8+ T cells from peripheral blood activated in the presence of TGF-β upregulated CD103 and secreted CXCL13. Conversely, inhibition of TGF-β receptor signaling abrogated CXCL13 production. Importantly, CXCL13+ CD103+ CD8+ TILs were strongly correlated with B cell recruitment, TLS and neo-antigen burden in six cohorts of human tumors. Altogether our findings indicate that TGF-β plays a non-canonical role in coordinating immune responses against human tumors and suggest a potential role for CXCL13+ CD103+ CD8+ TIL in mediating B cell recruitment and TLS formation in human tumors.
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