Immune Checkpoint Blockade Targeting the Novel PSGL-1/VISTA Axis for Pancreatic Cancer

Project Summary
The goal of this project is to develop a novel immunotherapy to treat PDAC based on blockade of PSGL-1 (P-
selectin glycoprotein ligand-1), to identify the attendant cellular and transcriptional changes in tumors comprising
high vs low T cell infiltration, and to determine whether resistance to current immune checkpoint blockade (ICB)
treatment can be overcome. PDAC is an aggressive cancer with an extremely poor prognosis that is highly
treatment refractory, including to ICB of PD-1 and CTLA-4, which may have limited effect part because these
tumors exhibit an immunologically ``cold'' tumor microenvironment (TME) with few CD8+ T cells. Dr. Bradley
identified P-selectin glycoprotein ligand (PSGL-1) as a T cell intrinsic checkpoint inhibitor. In vitro, PSGL-1 binds
to V-domain immunoglobulin suppressor of T cell activation (VISTA), which is a PD-L1 homologue that is the
most highly expressed inhibitory receptor in the PDAC TME. Of note, PSGL-1 deficiency promotes effector
activity of CD8+ T cells without development of terminal T cell exhaustion or widespread inflammation. The data
show the potential for PSGL-1 blockade to support progenitor-like cells (TPEX) that acquire effector functions and
respond to ICB therapy in other aggressive cancers. However, the impact of pharmacologically targeting the
PSGL-1/VISTA axis in PDAC is unknown. With orthotopic implantation of KPC.4662 PDAC tumor cells derived
from the KPC genetic mouse model of PDAC, PSGL-1-/- mice significantly control tumor growth, an outcome that
is linked to greater infiltration of CD8+ TPEX cells as well as VISTA+ immune cells. Notably, the CD8+ T cell anti-
tumor response is dependent upon CD4+ T cell help which Dr. Byrne, has shown enhances control of PDAC in
response to anti-CD40 treatment. In PSGL-1-/- mice, therapeutic PD-1 blockade eliminated KPC.4662 PDAC
tumors. Dr. Byrne has isolated KPC PDAC clones with distinct immune TMEs with T cell infiltrates ranging high
to low. T cell high tumors elicit innate immune cell activation in combination with chemotherapy and ICB. These
treatments are without effect in T cell low tumors, the dominant PDAC phenotype. The KPC PDAC clones display
variable VISTA expression, which will allow interrogation of its function on tumor cells. Together the data support
the premise that disrupting PSGL-1 and VISTA engagement may augment TEFF generation and sustain ICB
responsive TPEX that mediate tumor rejection. Therefore, we hypothesize that PSGL-1 blockade can provide
therapeutic benefit to overcome resistance of established PDAC to ICB. To test this hypothesis we propose
to 1) Interrogate the role of the PSGL-1/VISTA axis in regulating T cell responses; 2) Determine the immunologic
and therapeutic impact PSGL-1 blockade on T cell high and low PDAC tumor clones without and with other
treatment modalities; 3) Evaluate biomarkers of sensitivity to PSGL-1 targeting in patients with pancreatic cancer.
By extending these studies to human T cells, we envision that this project will address the possible clinical
potential of strategic targeting of PSGL-1.

Grant Number: 1R21CA293150-01A1
NIH Institute/Center: NIH
Principal Investigator: Linda Bradley