Decoding therapeutic, cross-presented tumor antigens in pancreatic cancer

University Of California Berkeley, Berkeley CA

Investigators

Abstract

Project Summary Identifying therapeutically efficacious tumor antigens remains a significant challenge in cancer vaccine development, as accurately predicting T cell responses from the bulk tumor immunopeptidome is difficult and costly to validate. Dendritic cells (DCs) play a pivotal role in eliciting anti-tumor T cell immunity, but their unique capacities to cross-present tumor antigens as a main driver of T cell infiltration in tumors have not been thoroughly investigated. This proposal aims to uncover the differences between the tumor immunopeptidome directly presented on cancer cells versus those cross-presented by DCs, and evaluate their contribution to T cell infiltration in tumors. I developed a mass spectrometry-based, antigen discovery platform that empirically identified peptides associated with MHC class I and II molecules on mouse DCs. This proposal will focus on pancreatic cancer, in which cancer-intrinsic and extrinsic mechanisms foster an immunosuppressive microenvironment and lead to T cell exclusion in the tumor. To determine whether immunosuppressive mechanisms impair effector T cell infiltration in tumors by modulating tumor antigen landscape on DCs, I will use in vitro and in vivo models combined with multi-omics approaches to decode DC antigen cross-presentation capacities in mouse and human pancreatic cancer. In Aim 1, I will compare cancer cell- and DC-presenting tumor immunopeptidomes in pancreatic cancer models with high- versus low-T cell infiltration, and test the hypothesis that cancer-intrinsic factors downregulate DC cross-presentation capacities and result in poor T cell infiltration in mouse pancreatic cancer (K99). In Aim 2, I will examine the impact of regulatory T cells (Tregs) on DC’s antigen presentation capacities as extrinsic mechanisms and identify tumor antigens whose presentation on DCs is enhanced following Treg ablation. I will then test the potential of Treg-downregulated antigens as cancer vaccine targets to improve anti-tumor T cell immunity and enhance tumor control (K99-R00). Aim 3 will extend these findings to human pancreatic cancer by examining the correlations between DC tumor antigen landscape and T cell infiltration in patient-derived models. Collectively, these multipronged studies will improve our understanding of cross-presented tumor antigens in driving immunosurveillance in pancreatic cancer and pave the way for novel cancer vaccination strategies. This research will be supported by a multidisciplinary advisory team in tumor immunobiology, including Drs. Michel DuPage (primary mentor, expert in cancer immunology and Treg biology), Joshua Elias (immunopeptidomics and mass spectrometry expert), and Ellen Robey (T cell development and antigen biology expert), and collaborators specializing in pancreatic cancer immunology. The exceptional resources and collaborative environment at UC Berkeley will foster my transition to independence and support my goal of advancing antigen discovery technologies for vaccine development against solid tumors.