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

• Published in: Cell reports (Cambridge) Vol. 28; no. 8; pp. 2140 - 2155.e6
• Main Authors: Burrack, Adam L., Spartz, Ellen J., Raynor, Jackson F., Wang, Iris, Olson, Margaret, Stromnes, Ingunn M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-08-2019; Elsevier
• Subjects: acquired resistance; Adenocarcinoma - immunology; Animals; Antigens, Neoplasm - immunology; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Carcinoma, Pancreatic Ductal - immunology; Cell Line, Tumor; Disease Models, Animal; Histocompatibility Antigens Class I - metabolism; Immune Evasion; Immunity, Cellular; Immunodominant Epitopes - immunology; Immunotherapy; Interferon-gamma - metabolism; Mice, Inbred C57BL; neoepitope; pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - immunology; PD-1; PD-L1; PDA; Phenotype; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Signal Transduction; T cells; T-Lymphocytes - immunology; pancreatic cancer; neoepitope; immunotherapy; PD-L1; PDA; T cells; PD-1; acquired resistance
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.059

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.
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•A peptide:MHC tetramer is created to study pancreas cancer-specific T cells•PD-L1 blockade expands peripheral T cells required for antitumor efficacy•Tumor escape variants defective in IFNγ-inducible Tap1 and MHC class I emerge•PD-1 + PD-L1 blockade enhances T cell functionality and longevity and promotes cure
Burrack et al. investigate tumor-specific T cells during immunotherapy of pancreas cancer. T cells accumulate intratumorally yet rapidly exhaust. Combined PD-1 + PD-L1 blockade promotes peripheral T cell expansion, TNFα production, and eradication of spontaneous tumor recurrence in 50% of animals. Tumor variants defective in IFNγ-inducible Tap1 and MHC class I ultimately emerge.