Role of Antigen Strength in Regulating Tumor

To understand how antigenic strength regulates the manifestations of tumor immune editing, equilibrium, and escape using genetically engineered mouse models of cancer.


  • Determine antigenic threshold, class I vs. II dependency, and role of central and peripheral tolerance in achieving T cell response, tumor rejection, and cure.
  • Determine pathways of immune escape when antigen expression is preserved, uncovering the role of tumor cell intrinsic pathways, antigen presentation and tumor microenvironment
  • Model T cell response in vivo to tumor cells engineered neo-antigens encompassing range of mutations and putative TCR affinities
  • Compare the pMHC repertoire of APC vs. tumor cells, and regulation
  • Determine antigenic and immunogenic landscapes of human cancer with novel bioinformatics tools and available large data sets


  • We re-evaluated the main tenets of immunoediting and T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy. In contrast to these immunogenic tumor models from which the “triple E” theory was surmised, we found no evidence for immunoediting in a mutant Kras-driven murine model of PDA. Findings suggest an alternative biological mechanism in which tumor outgrowth reflects immune quiescence, which is linked to, and regulated by, poor tumor antigenicity — a conclusion with potential relevance to human cancers with a low burden of mutations and minimal neoepitopes.
  • Using bioinformatics tools and TCGA data, we have performed immune profiling of human primary pancreatic cancer
  • We have profiled BRCA1/2 mutant breast tumors immunologically using NGS and tissue microarrays to connect mutational burden, neoepitope levels, and immune content and checkpoint signatures with levels of HRD and status of allele specific LOH, demonstrating that tumor genetics around BRCA and not neo epitope drives immunity in these tumors
  • We report a novel class of neo-epitopes based on differential agretopicity that outperforms classically defined neoepitopes for immunity and surivival looking across the entire TCGA database
  • We assessed the prevelance of Kras mutations and common HLA types using TCG
  • We established an “app” called Antigen.Garnish that connects users to a bioinformatics pipeline for neo-epitope prediction, including fusions and frameshifts, for mouse and human tumors.

Evans et al, JCI Insight, 2016

Balli et al, Clin Cancer Res, 2016

Rech and Vonderheide, NEJM, 2017

Project Participants: Robert Vonderheide, Andrew Rech, Mark Diamond, Lee Richman, Jeffrey Lin, Katelyn Byrne (Parker Fellow), Ben Stanger, and Kate Nathanson