Layilin augments integrin activation to promote antitumor immunity.

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 alpha L beta 2 (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.