Layilin augments integrin activation to promote antitumor immunity
Kelly M. Mahuron, J. Moreau, Jeff E. Glasgow, Devi P Boda, Mariela Pauli, Victoire Gouirand, Luv Panjabi, Robby Grewal, Jacob M. Luber, Anubhav Mathur, R. M. Renny Feldman, Eric Shifrut, Pooja Mehta, Margaret M. Lowe, Michael Alvarado, Alexander Marson, Meromit Singer, Jim Wells, Ray Jupp, Adil Daud, Michael D. Rosenblum
Abstract
Tumor-infiltrating CD8+ T cells mediate antitumor immune responses. However, the mechanisms by which T cells remain poised to kill cancer cells despite expressing high levels of inhibitory receptors are unknown. Here, we report that layilin, a C-type lectin domain-containing membrane glycoprotein, is selectively expressed on highly activated, clonally expanded, but phenotypically exhausted CD8+ T cells in human melanoma. Lineage-specific deletion of layilin on murine CD8+ T cells reduced their accumulation in tumors and increased tumor growth in vivo. Congruently, gene editing of LAYN in human CD8+ T cells reduced direct tumor cell killing ex vivo. On a molecular level, layilin colocalized with integrin αLβ2 (LFA-1) on T cells, and cross-linking layilin promoted the activated state of this integrin. Accordingly, LAYN deletion resulted in attenuated LFA-1-dependent cellular adhesion. Collectively, our results identify layilin as part of a molecular pathway in which exhausted or "dysfunctional" CD8+ T cells enhance cellular adhesiveness to maintain their cytotoxic potential.