Immunotherapy, a type of treatment aimed at engaging the immune system – namely, T cells – to attack and kill cancer cells, has had success and redefined care in multiple types of cancer, including melanoma and lung cancer. Unfortunately, pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, has largely been resistant to this type of treatment. Understanding why PDAC tumors don’t respond to immunotherapy can lead to opportunities to reverse this resistance and generate better outcomes for PDAC patients.
Katelyn T. Byrne, Ph.D, Assistant Professor of Cell, Developmental, and Cancer Biology at OHSU School of Medicine and a member of the OHSU Brenden-Colson Center for Pancreatic Care, has focused her lab to evaluate how the tumor microenvironment of PDAC tumors suppresses the immune system and therapeutic mechanisms that can help overcome their resistance to immunotherapy. Her project, Interrogating the role of PSGL1/VISTA axis in the pancreatic tumor-immune microenvironment, was awarded a 2024 Hirshberg Foundation Seed Grant to study the role the immune cell suppressing protein PSGL-1 plays in PDAC’s resistance to immunotherapy.
PSGL-1 is a protein expressed on T cells that inhibits T cell activation, function, and migration into tissues. VISTA is a protein that is known to bind PSGL-1 and is found highly expressed in the tumor microenvironment of PDAC tumors. Over the past year, Dr. Byrne’s group has evaluated the role of this pathway in promoting immune suppression via T cell dysfunction using both preclinical models and patients’ samples. Their data suggests a role PSGL-1 may regulate immune suppression in the PDAC tumor microenvironment, and that targeting of PSGL-1 may provide therapeutic benefits in preclinical models.
The Byrne lab also profiled a cohort of PDAC patient tumor samples for expression of PSGL-1, and found that T cells that express high levels of PSGL-1 have low levels of other T cell dysfunctional markers that are targeted by current immunotherapies, one potential reason that current treatments ‘don’t work’ in pancreatic cancer. PSGL-1-expressing T cells also had increased cell-cell interactions that may be important for PSGL-1 mediated suppression in the tumor microenvironment of PDAC tumors.
This work is still in progress and continuing work will focus on understanding PSGL-1 suppresses an anti-tumor immune response, understanding how best to target PSGL-1 for therapeutic benefit in patients, and how to best combine PSGL-1 targeted therapy with other therapies for pancreatic cancer to increase the response and quality of life for these patients. Dr. Byrne will be sharing this work in October at the Hirshberg Foundation-UCLA Research Forum on Pancreatic Cancer Research.
