TGFβ signaling intersects with CD103 integrin signaling to promote T-Lymphocyte accumulation and antitumor activity in the lung tumor microenvironment

Homing of CD8+ T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGFβ is responsible for CD103 (αEβ7) integrin induction in activated intraepithelial CD8+ T lymphocytes. However, the interplay between TGFβ 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, TGFβ enhanced CD103-dependent Tcell 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 TGFβ bound to its receptors (TGFβR), which promoted the recruitment and phosphorylation of integrinlinked kinase (ILK) by TGFβR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin insideout signaling. Collectively, our findings suggest that the abundance of TGFβ 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.