Tgf Beta 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. TGF beta is responsible for CD103 (alpha(E)beta(7)) integrin induction in activated intraepithelial CD8(+) T lymphocytes. However, the interplay between TGF beta 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 beta enhanced CD103-dependent T-cell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (alpha(L)beta(2)) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGF beta 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 beta 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.