PSGL-1 deficiency re-wires T cell signaling to support development of stem cell like exhausted T cells that control PD-1 blockade resistant melanoma tumor growth

Abstract We previously identified that the adhesion molecule P-selectin glycoprotein ligand-1 (PSGL-1) regulates CD8 +T cell effector functions and promotes exhaustion in responses to chronic viral infection melanoma tumors. In this study, we investigated cellular molecular mechanisms by which intrinsic PSGL-1 signaling differentiation of exhausted T cells (T EX). show localizes with TCR upon co-ligation find associates Zap70 inhibitor, Sts-1. absence PSGL-1, expression Sts-1 is reduced allowing for greater activation downstream molecules Akt Erk1/2. addition, PSGL-1-deficiency empowers respond low affinity ligands. vivo, deficiency leads growth inhibition a PD-1-blockade resistant melanoma. Notably, enables retention EFF) functions, an increased representation stem cell-like SC) express TCF-1 levels TOX, are associated sustained responsiveness ICB. now concomitant repeated stimulation human EFFelicits functional exhaustion. Importantly, blockade recapitulates anti-tumor as well antiviral responses, its distinct mechanism underscores translational potential targeting Supported grants from NIH (R01 AI106895, R21 CA249353, CA216678, R03 CA252144) Melanoma Research Alliance MRA 696326, Department Defense W81XWH-20-1-0324, Sanford Burnham Prebys NCI-Designated Cancer Center Support Grant, P30 CA030199 American Society Postdoctoral Fellowship (PF-20-113-01-LIB)