Abstract IA003: Targeting the antigenic landscape that emerges after KRAS inhibition for PDAC immunotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is predicted to emerge as the second leading cause of cancer related death by 2030. Many treatment options that are successful in other cancer types, including immune checkpoint blockade, are generally ineffective in PDAC and the 5-year survival rate has remained stagnant for decades. Mutant KRAS, the most common oncogenic driver in PDAC, was previously considered “undruggable” but recent advances have led to the development of potent KRAS inhibitors (KRASi) that have demonstrated unprecedented clinical activity. While KRASi has shown early promise, inherent and acquired resistance remains a significant clinical barrier. Notably, preclinical studies have shown that KRASi induces T cell mediated anti-tumor immunity, but the mechanisms driving this phenomenon are unknown. T cell recognition of cancer occurs through the presentation of antigens on Major Histocompatibility Complexes (MHC-I and MHC-II). Despite the recognition that KRASi drives adaptive immunity in PDAC, the functional interplay between KRASi and antigen presentation has not been explored. Therefore, we hypothesized that KRASi reshapes both the MHC-I and MHC-II antigen landscape in the PDAC tumor microenvironment to drive anti-tumor immune responses. To address this, we utilized a collection of novel preclinical mouse models and patient derived organoids (PDOs) to identify treatment induced patterns of antigen presentation on MHC-I and MHC-II on malignant and stromal cells. KRASi induced the presentation of numerous epitopes on both MHC-I and MHC-II, many of which are known to be associated with adaptive resistance to KRASi. We also observed that tumors that exhibited strong responses to KRASi induced MHC-II, indicating a favorable tumor immune microenvironment marked by malignant cell derived MHC-II. Many KRASi induced MHC-II epitopes were found to be highly immunogenic, suggesting that CD4+ T cells targeting MHC-II epitopes are an underappreciated source of immunotherapeutic potential in PDAC. Cross species analysis of MHC epitopes induced by KRASi in human and mouse cells revealed conserved antigenic landscapes for future therapeutic development. These studies hold significant translational potential as KRAS inhibitors are poised to become a mainstay in PDAC treatment and treatment induced antigens may serve as the foundation for rationally designed combination immunotherapies.