A Transcriptionally Distinct CXCL13+CD103+CD8+ T-cell Population Is Associated with B-cell Recruitment and Neoantigen Load in Human Cancer

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 TGF beta-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 beta upregulated CD103 and secreted CXCL13. Conversely, inhibition of TGFb receptor signaling abrogated CXCL13 production. CXCL13(+) CD103(+)CD8(+) TILs correlated with B-cell recruitment, TLSs, and neoantigen burden in six cohorts of human tumors. Altogether, our findings indicated that TGFb plays a noncanonical role in coordinating immune responses against human tumors and suggest a potential role for CXCL13(+)CD103(+)CD8(+) TILs in mediating B-cell recruitment and TLS formation in human tumors.