TGF-β signaling intersects with CD103 integrin signaling to promote T lymphocyte accumulation and antitumor activity in the lung tumor microenvironment

Abstract : Homing of CD8+ T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGF-β is responsible for CD103 (αEβ7) integrin induction in activated intraepithelial CD8+ T lymphocytes. However, the interplay between TGF-β and CD103 and their contribution to T-cell infiltration and antitumor activity remain unknown. Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Moreover, TGF-β enhanced CD103-dependent T-cell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (αLβ2) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGF-β bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation thereby initiating integrin inside-out signaling. Collectively, our findings suggest that the abundance of TGF-β in the tumor microenvironment may in fact engage with integrin signaling pathways to promote T-lymphocyte antitumor functions, with potential implications for T-cell-based immunotherapies for cancer
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Cancer Research, American Association for Cancer Research, 2016, 76 (7), pp.1757-69. 〈10.1158/0008-5472.CAN-15-1545〉
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Marie Boutet, Ludiane Gauthier, Marine Leclerc, Gwendoline Gros, Vincent De Montpreville, et al.. TGF-β signaling intersects with CD103 integrin signaling to promote T lymphocyte accumulation and antitumor activity in the lung tumor microenvironment. Cancer Research, American Association for Cancer Research, 2016, 76 (7), pp.1757-69. 〈10.1158/0008-5472.CAN-15-1545〉. 〈hal-01282442〉

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