PD-L1/PD-1 Immunotherapy Modulates Effector T Cells Homeostasis and Function in Murine Pancreatic Cancer

Abstract

Pancreatic Cancer (PC) is one of the most aggressive and deadliest types of cancer, and it is projected to be the second leading cause of cancer-related deaths in the U.S. by the year 2030. PC evades immune surveillance by disrupting the immune homeostasis of effector T cells (Teff). T cells homeostasis is critical for proper anti-tumor immune responses. Preliminary flow cytometry data revealed that murine pancreatic (Panc02) cancer cells produce inflammatory soluble factors and in addition, express Major Histocompatibility Complex class I (MHC-I) and Programmed Death Ligand 1 (PD-L1) and 2 (PD-L2). PD-L1/2 can bind to PD-1 receptors on Teff and induce apoptosis or anergy, dampening the anti-tumor immunity. Cytokine bead array and flow cytometry analysis of serum from peripheral blood from C57BL/6 mice injected with Panc02 cells (TB mice) showed a significant increase in inflammatory factors compared to Control (CTRL) mice. Additionally, Teff from splenocytes from TB mice showed significant reduction in Teff percentages compared to CTRL mice, in vitro. In this study, CD3+ cells from CTRL mice were co-incubated with Panc02 cells pre-treated with anti-PD-L1 antibody (ab) to evaluate the modulation of Teff and cytokines production, in vitro. Mice were inoculated with the Panc02 pre-treated cells with anti-PD-L1 ab, to evaluate the modulation of Teff and cytokines production, in vivo. The results from this project may lead to the identification of new immunotherapeutic strategies to stabilize Teff homeostasis and function that could increase anti-tumor immune responses and combat PC progression.