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Layilin augments integrin activation to promote antitumor immunity.

  • Author(s): Mahuron, Kelly M;
  • Moreau, Joshua M;
  • Glasgow, Jeff E;
  • Boda, Devi P;
  • Pauli, Mariela L;
  • Gouirand, Victoire;
  • Panjabi, Luv;
  • Grewal, Robby;
  • Luber, Jacob M;
  • Mathur, Anubhav N;
  • Feldman, Renny M;
  • Shifrut, Eric;
  • Mehta, Pooja;
  • Lowe, Margaret M;
  • Alvarado, Michael D;
  • Marson, Alexander;
  • Singer, Meromit;
  • Wells, Jim;
  • Jupp, Ray;
  • Daud, Adil I;
  • Rosenblum, Michael D
  • et al.
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.

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