TGFβ Signaling Intersects with CD103 Integrin Signaling to Promote T-Lymphocyte Accumulation and Antitumor Activity in the Lung Tumor Microenvironment

Abstract

Homing of CD8þ T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGFb is responsible for CD103 (a E b 7 ) integrin induction in activated intraepithelial CD8 þ T lymphocytes. However, the interplay between TGFb 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, TGFb enhanced CD103-dependent Tcell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (a L b 2 ) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGFb bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrinlinked 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 insideout signaling. Collectively, our findings suggest that the abundance of TGFb 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. Cancer Res; 76(7); 1757-69. Ó2016 AACR.

CD103+ CD8 T Cells in the Toxoplasma-Infected Brain Exhibit a Tissue-Resident Memory Transcriptional Profile

“…The TGF-β receptor was upregulated (FC = 2.75) in brain CD103 + CD8 T cells, consistent with previous reports of the requirement for TGF-β in generation of this population (46, 47). Notably, the pro-inflammatory cytokine Tnf is significantly upregulated in CD103 + CD8 T cells (FC = 2.5 relative to brain CD103 − ) (Figures 4B–D; Figure S5 in Supplementary Material).…”

“…Expression of CD103 can define a resident memory T cell, yet the T RM phenotype is not restricted to CD103 expression, nor is CD103 expression exclusive to this subset (13, 47, 49–51). This is seen in our data with flow cytometry and immunohistochemistry data revealing expression of CD103 by CD4 + T cells and dendritic cells in the Toxoplasma -infected brain and CD8 + T cells (Figure 2; Figure S7 in Supplementary Material and data not shown) (52, 53).…”

Resident memory T cells, critical components in tumor immunology

“…Consistently, studies performed with viable human tumor slices [30] and autologous tumor antigen-specific CTL clones showed that CD103 contributes to T-cell recruitment within epithelial tumor regions and enhances intratumoral T-cell early signaling [31]. Indeed, recruitment of CD8 + T lymphocytes within epithelial tumor islets was inhibited by anti-CD103 neutralizing monoclonal antibodies (mAb), while TGF-β enhanced CD103-dependent T-cell movement toward epithelial tumor regions [31]. In this context, studies from one of our groups showed that CD103 mediates arrest of T lymphocytes under flow by interacting with E-cadherin on epithelial tumors [32].…”

“…The intra-epithelial location of CD103 + CD8 + T cells was also observed in colorectal and bladder cancers, and was associated with expression of E-cadherin on tumor cells [28, 29]. Consistently, studies performed with viable human tumor slices [30] and autologous tumor antigen-specific CTL clones showed that CD103 contributes to T-cell recruitment within epithelial tumor regions and enhances intratumoral T-cell early signaling [31]. Indeed, recruitment of CD8 + T lymphocytes within epithelial tumor islets was inhibited by anti-CD103 neutralizing monoclonal antibodies (mAb), while TGF-β enhanced CD103-dependent T-cell movement toward epithelial tumor regions [31].…”

“…2). Indeed, TGF-β triggers TGFΒR1-mediated phosphorylation of ILK and its subsequent binding to the integrin intracellular domain, resulting in AKT phosphorylation and thereby initiating inside-out signaling that leads to increased CD103 affinity for its ligand E-cadherin [31]. Firm adhesion of CD103 to E-cadherin triggers phosphorylation of Pyk2 protein tyrosine kinase and the paxillin adaptor protein, and subsequent binding of phosphorylated-paxillin to the CD103 cytoplasmic domain, initiating outside-in signaling that promotes CD8 + T RM migratory behavior and effector functions [63].…”