TRAF6 signaling pathway in T cells regulates anti-tumor immunity through the activation of tumor specific Th9 cells and CTLs

CD8(+) cytotoxic T lymphocytes (CTLs) and CD4(+) helper T (Th) cells play a critical role in protective immune responses to tumor cells. Particularly, Th9 cells exert anti-tumor activity by producing IL-9. TNF receptor (TNFR)-associated factor 6 (TRAF6) is an adaptor protein that mediates the signals from both the TNFR superfamily and Toll-like receptors (TLRs). We have previously reported that T cell-specific TRAF6deficent (TRAF6 Delta T) mice spontaneously developed systemic inflammatory diseases. However, the physiological role of TRAF6 in T cells in controlling anti-tumor immune responses remains largely unclear. Here, we found that tumor formation of syngeneic colon cancer cells inoculated in TRAF6 Delta T mice was accelerated compared to that in control mice. Although TRAF6-deficient naive T cells showed enhanced differentiation of Th9 cells in vitro, these T cells produced lower amounts of IL-9 in response to a specific antigen. Moreover, CD4(+) tumor-infiltrating lymphocytes (TILs) in tumor-bearing TRAF6 Delta T mice expressed lower levels of IL-9 than those in WT mice. Importantly, administration of recombinant IL-9 (rIL-9) strongly suppressed tumor progression in TRAF6 Delta T mice. Furthermore, expression levels of the T-box transcription factor Eomesodermin (Eomes) and its target molecules IFN-gamma, granzyme B and perforin, as well as cytotoxic activity, were reduced in TRAF6-deficient CD8(+) T cells in vitro. TRAF6-deficient T cells were found to express significantly increased levels of immune checkpoint molecules, CTLA-4 and PD-1 on the cell surface. These results demonstrate that the TRAF6 signaling pathway in T cells regulates anti-tumor immunity through the activation of tumor specific Th9 cells and CTLs in a tumor microenvironment. (C) 2022 Elsevier Inc. All rights reserved.