Layilin augments integrin activation to promote antitumor immunity.

The Journal of Experimental Medicine
Kelly M MahuronMichael 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.

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Citations

Mar 3, 2021·The Journal of Experimental Medicine·Kristen E PaukenMeromit Singer
Jul 17, 2021·Trends in Immunology·Audrey GérardRobert Köchl
Sep 3, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Pooja MehtaMichael D Rosenblum

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Datasets Mentioned

BETA
GSE147620
GSE148190

Methods Mentioned

BETA
FACS
RNA-seq
scRNA-seq
PCR
flow cytometry
ELISA
PMA
proximity ligation
biopsy
FCS

Software Mentioned

SAMtools
Bioconductor
R
Ensembl
ggplot2
Seurat
TopHat
R package Pretty Heatmaps
GraphPad
Prism

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