Abstract A051: PSGL-1-deficiency promotes pancreatic ductal adenocarcinoma tumor control and synergy with immune checkpoint blockade
Authors: Hope Jennifer L. , Zhang Yijuan , Faso Hannah A. , Roy Sreeja , Lin Michelle , Palete Ashley B. , Maganti Swetha , Otero Dennis C. , Commisso Cosimo , Bradley Linda M. 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, poorly immunogenic cancer with increasing incidence rates while patient prognosis remains poor with a 5-year survival rate of only 12%. PDAC tumors are refractory to all currently available treatments, including existing immune checkpoint blockade (ICB) therapies, and demonstrate limited T cell infiltration. There is a critical need to develop novel approaches to improve patient outcomes. We previously demonstrated that deficiency of P-selectin glycoprotein 1 (PSGL-1) promotes enhanced T cell responses that clear chronic LCMV Cl13 virus infection and inhibit growth of PD-1 blockade resistant melanoma. Here we evaluated if targeting PSGL-1 promotes T cell responses to PDAC tumors to inhibit growth and metastases. KPC.4662 tumor cells were injected orthotopically into the tail of the pancreas of C57BL/6 (wildtype control) and PSGL-1−/− (C57BL/6 background) male or female mice and tumor growth and immune infiltration was evaluated by histology and flow cytometry. At 28 days post-orthotopic tumor cell injection, KPC.4662 tumor burden was reduced by 50% on average (1.1 g vs 0.45g) in PSGL-1−/− mice compared to controls. Total immune infiltration (CD45+) was increased in tumors from PSGL-1−/- mice (10% vs 24%), with a significant increase in CD3+ T cell infiltration. Moreover, fewer mice developed metastases in the peritoneal cavity, liver, and lungs. To assess if PSGL-1−/− mice had the capability to reduce metastatic burden, KPC 4662 tumor cells were injected intravascularly and tumor development in the lungs was assessed on day 17. PSGL-1−/− mice reproducibly developed fewer tumors in the lungs compared to wildtype control mice as determined by histological examination. To address if enhanced control of PDAC tumors was mediated by T cells, we depleted CD4+ and CD8+ T cells immediately prior to orthotopic implantation of KPC.4662 tumor cells. Depletion of T cells resulted in the loss of PDAC tumor growth control in PSGL-1−/− mice. Given our previous studies demonstrating an intrinsic role for PSGL-1 in the development of T cell exhaustion, we hypothesized that PSGL-1-deficiency would promote responsiveness to PD-1 immune checkpoint blockade, a therapy known to be ineffective as a monotherapy in PDAC patients and mouse models. When PD-1 blocking antibody was therapeutically administered on days 10, 12, and 14 post-tumor implantation, 85% of PSGL-1−/− animals demonstrated complete responses. From these studies, we conclude that in the absence of PSGL-1, we observe significantly reduced growth of primary orthotopic PDAC tumors and decreased metastases. These findings are associated with increased CD45+ immune cell infiltration in the tumors and notably functions in a T cell-dependent manner. PSGL-1 therefore represents a novel target for promoting immune responses to PDAC tumors.
Citation Format: Jennifer L. Hope, Yijuan Zhang, Hannah A. Faso, Sreeja Roy, Michelle Lin, Ashley B. Palete, Swetha Maganti, Dennis C. Otero, Cosimo Commisso, Linda M. Bradley. PSGL-1-deficiency promotes pancreatic ductal adenocarcinoma tumor control and synergy with immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A051.