Investigation of Immunotherapy-induced Alterations to Cellular Communication Networks in Pancreatic Ductal Adenocarcinoma

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer in the United States. The low mutational burden in PDAC leads to low infiltration of T cells that could become cytotoxic to cancer cells by administration of immune checkpoint inhibitors (ICIs). Neoantigen vaccines promote T cell invasion, but do not protect T cells from exhaustion. Analysis of immunotherapy approaches to clinical treatment of PDAC combining cancer vaccines with ICIs suggests that efficacious immune response involves alterations in cell-cell communication among tumor-invading immune cells. Murine models of neoantigen response indicate that simultaneous priming of tumor-specific CD8+ and CD4+ T cells increases survival through CD4+ T cell-dependent enhancement of anti-tumor CD8+ T cell and myeloid cell functions. I hypothesize that effective immunotherapy response in PDAC is dependent on altering cellular signaling networks in the tumor microenvironment to maintain durable cytotoxic effector states and hinder immunosuppressive signals. To test this hypothesis, I will utilize single-cell RNA sequencing (scRNA-seq) data from a compiled atlas of immunotherapy-naïve PDAC, primary tumors from a neoadjuvant trial of combination immunotherapy for PDAC, and a murine model of personalized neoantigen vaccine treatment for PDAC. Experiments posed in Aim 1 will develop statistical methods for the utilization of the cellular communication inference tool Domino in identifying cellular interactions that differentially occur between treatment groups in scRNA-seq data from clinical trials of combination immunotherapy in humans. Experiments posed in Aim 2 will identify the mechanism by which the tumor-specific T cells expanded by the neoantigen vaccine PancVAX2 attack liver metastases in an orthotopic murine model of PDAC through flow cytometry and inference of cell- cell communication in scRNA-seq data. Collectively, these experiments will inform mechanistic understanding of how combination immunotherapies enhance immune responses to PDAC through enhancement of T cell cytotoxicity and alterations of communication between immune cells. This proposed work will have broad applications improving immunotherapy approaches to the treatment of PDAC and develop computational tools for scRNA-seq analysis to assess how cellular communication is altered by outside perturbations and sample features.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic ductal adenocarcinoma is a highly deadly cancer with the potential for improved outcomes in patient survival using combination immunotherapies. This research seeks to investigate the mechanisms of how these therapies alter the communication between immune cells to recognize and fight this cancer. Understanding these mechanisms will result in better treatments that utilize the immune system to eradicate cancer and lead to fewer deaths from this disease.