Combination PD-1 and PD-L1 Blockade Promotes Durable Neoantigen-Specific T Cell-Mediated Immunity in Pancreatic Ductal Adenocarcinoma

Adam L Burrack1, Ellen J Spartz2, Jackson F Raynor1, Iris Wang1, Margaret Olson1, Ingunn M Stromnes3

  1. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
  2. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
  3. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Masonic Cancer Center of the University of Minnesota Medical School, Minneapolis, MN 55455, USA. Electronic address: ingunn@umn.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptide:MHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhances systemic T cell expansion and induces objective responses that require systemic T cells. However, tumor escape variants defective in IFNγ-inducible Tap1 and MHC class I cell surface expression ultimately emerge. Combination PD-1 + PD-L1 blockade synergizes therapeutically by increasing intratumoral KLRG1+Lag3-TNFα+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recurrence, thereby prolonging animal survival. Our studies support that PD-1 and PD-L1 are relevant immune checkpoints in PDA and identify a combination for clinical testing in those patients with neoantigen-specific T cells.

Presented By Adam Burrack

Cancer Biology, Immunology & MicrobiologyNicholas Liao2019-08 (Aug)