PSGL-1 deficiency eradicates orthotopic pancreatic ductal adenocarcinoma tumors in combination with anti-PD-1 therapy and enhances T cell anti-tumor immunity

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is highly refractory to all current immune checkpoint blockade (ICB) therapies and display limited CD8 +T cell infiltration. We previously showed that deficiency of P-selectin glycoprotein 1 (PSGL-1) promotes CD8 +T cell responses that clear chronic lymphocytic choriomeningitis virus (LCMV) Cl13 virus infection and dramatically inhibits the growth of anti-PD-1 blockade resistant melanoma. Here we evaluated if PSGL-1 regulates CD8 +T cell responses to PDAC tumors. Results: PSGL-1 −/−mice reproducibly showed T cell dependent, significant reduction of KPC.4662 primary PDAC tumors and reduced metastasis to lungs compared to control mice. Furthermore, anti-PD-1 treatment of PSGL-1 −/−mice completely obliterated tumor growth as opposed to control mice. Histology of primary tumors revealed marked increase of immune infiltration (CD45 +cells), including CD3 +T cells in PSGL-1 −/−mice. Flow cytometry and immunofluorescence staining confirmed a significant increase in tumor-infiltrating CD8 +T cells in PDAC tumors from PSGL-1 −/−mice. Importantly, PSGL-1 −/−CD8 +T cells were phenotypically and functionally less exhausted. Conclusion: PSGL-1 deficiency significantly reduced growth of primary orthotopic PDAC tumors and decreased metastases and this effect was enhanced in combination with anti-PD-1 ICB treatment. This protective effect was associated with increased immune cell infiltration in the tumors and notably, increased CD8 +T cell effector responses. PSGL-1 therefore represents a novel target for promoting immune responses to PDAC tumors and responses to PD-1 blockade. NCI Cancer Center Support Grant P30 CA030199