Paxillin Binding to the Cytoplasmic Domain of CD103 Promotes Cell Adhesion and Effector Functions for CD8⁺ Resident Memory T Cells in Tumors.

Abstract

CD8⁺/CD103⁺ tissue-resident memory T cells (T_RM cells) accumulate in several human solid tumors, where they have been associated with a favorable prognosis. However, the role of CD103, the α subunit of the integrin α_Eβ₇ (also known as CD103), in the retention and functions of these T_RM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through α_E/CD103 chain. Binding to immobilized recombinant (r)E-cadherin-Fc of CD103 integrin expressed on tumor-specific CTL clones promotes phosphorylation of Pxn and Pyk2 and binding of Pxn to the α_E/CD103 subunit tail. Inhibition of Pxn phosphorylation by the Src inhibitor saracatinib or its knockdown via shRNA dramatically altered adhesion and spreading of freshly isolated CD8⁺/CD103⁺ lung tumor-infiltrating lymphocytes and CD103⁺ tumor-specific CTL clones. Inhibition of Pxn phosphorylation with saracatinib in these CTL clones also severely compromised their functional activities toward autologous tumor cells. Using Jurkat T cells as a model to study CD103 integrin activation, we demonstrated a key role of serine residue S1163 of the α_E chain intracellular domain in polarization of CD103 and recruitment of lysosomes and Pxn at the contact zone of T lymphocytes with rE-cadherin-Fc-coated beads. Overall, our results show how Pxn binding to the CD103 cytoplasmic tail triggers α_Eβ₇ integrin outside-in signaling that promotes CD8⁺ T-cell migratory behavior and effector functions. These results also explain the more favorable prognosis associated with retention of T_RM cells in the tumor microenvironment. <i>Cancer Res; 77(24); 7072-82. ©2017 AACR</i>.