PSGL-1 directs early TCR signaling to repress metabolism and promote T cell exhaustion by modulating the TCF-1/TOX axis in CD8⁺ T cells

Abstract

We previously identified the adhesion molecule PSGL-1 as a T cell intrinsic immune checkpoint regulator of T cell exhaustion. Here we show that the ability of PSGL-1 to restrain TCR sginaling correlates with decreased expression of the Zap70 inhibitor Ubash3b (Sts-1) in PSGL-1-deficient T cells. PSGL-1-deficency in T cells supports antitumor responses to a PD-1 blockade resistant melanoma wherein tumor-specific CD8+ T cells sustain an enhanced metabolic state, with an elevated metabolic gene signature that promotes increased glycolysis and glucose uptake to support effector functions. In models of chronic virus infection and cancer, this outcome was associated with CD8+ T cell stemness, as PSGL-1 deficient CD8+ T cells displayed increased TCF-1 and decreased TOX expression, a phenotype shown to be crucial for responsiveness to checkpoint inhibition. Further, we demonstrate that PSGL-1 signaling promotes development of exhaustion in human CD8+ T cells. Finally, pharmacologic blockade of PSGL-1 was sufficient to curtail T cell exhaustion and enhance functionality both with melanoma tumors and chronic LCMV infection, demonstrating that PSGL-1 represents a therapeutic target for immunotherapy for PD-1/PD-L1 resistant tumors.

Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early stage NSCLC.

“…Beyond adhesion, PSGL-1 has been shown to be implicated in T cell signaling pathways, in uencing cytokine production and immune suppression within the TME [30]. Furthermore, recent data support that the therapeutic blockade of PSGL-1 may promotes T cell responses and melanoma tumor control [24].…”

“…In recent years, along with PD-1 and CTLA-4, other immune modulators able to rewire the immune response within the TME have been taken into account. Indeed, V-domain Ig suppressor of T-cell activation (VISTA), an inhibitory immune checkpoint molecule, and its ligand P-selectin glycoprotein ligand-1 (PSGL-1, also known as CD162) multifunctional glycoprotein, have garnered attention for their roles in modulating immune cell function, angiogenesis, and tumor progression [21][22][23][24][25][26][27][28][29][30][31].…”