Antigen-specific CD4 T cell polarization is altered by immune checkpoint blockade in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with poor response to conventional immune checkpoint inhibitors. Early data by our group suggests CD4 T cell depletion abrogates response to a novel combination therapy that is transiently curative in a murine model of PDA. Given the importance of CD4 T cells in PDA control, we now seek to describe CD4 T cell dynamics in PDA at an antigen-specific resolution. To this end, we developed a novel tetramer reagent towards a recently identified MHC class II model epitope. Through this, we observe antigen-specific T-cell polarization that is distinct from the bulk CD4 population both in the spleen and in the tumor microenvironment. Tumor-specific CD4 T cells also displayed differential polarization during combination therapy, suggesting positive response to therapy is mediated in part by TCR-dependent stimulation of the CD4 compartment.