Abstract PO-063: Functional interrogation of immune escape in neoantigen-expressing pancreatic cancer identifies a critical role for the CD155/TIGIT axis

Abstract

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. While insights regarding mechanisms of immune escape have fueled tremendous clinical successes in a broad range of tumor types, microsatellite-stable pancreatic adenocarcinoma (PDAC), which represents greater than 98% of patients, is largely refractory to available immune checkpoint blockade. The recent recognition that a subset of pancreas cancer harbors potential neoantigens has intensified interest in defining the molecular and cellular mechanisms of immune evasion in PDAC to guide effective therapeutic strategies that leverage the adaptive immune system in this disease. However, difficulty in precisely defining the tumor-reactive T cell compartment has hampered prior efforts to delineate the full spectrum of mechanisms by which PDAC evades immune eradication. We recently developed multiple organoid-based and autochthonous preclinical models to delineate the molecular and cellular mechanisms of immune evasion in this subset of patients. Specifically, we utilized a high affinity MHC class I-restricted antigen (OVA257–264) or recently described missense-derived MHC class I-restricted neoantigens (mutations in the laminin 4 alpha subunit or in alpha-1,3-glucosyltransferase). While a subset of animals either successfully clear these tumors, or are arrested in a state of immune-mediated tumor dormancy, all three neoantigen models lead to a significant subset of tumors that acquire the ability to evade immune clearance. In these preclinical models, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, typified by T cell exhaustion (best marked by TIGIT+PD1+ co-positivity). Global profiling of the tumor-immune microenvironment in neoantigen-expressing murine PDAC compared to non-neoantigen-expressing PDAC identified an expected increase in CD8+ T cells, and specifically in neoantigen-specific CD8+ T cells, but also identified additional changes within the broader leukocyte contexture. Using flow cytometric and single-cell transcriptomic analyses, we demonstrate that human PDAC TILs express similar dysfunctional programs and are enriched in TIGIT+PD1+ TILs. Furthermore, we show that CD155, the high affinity TIGIT ligand, is highly expressed on the surface of murine and human PDAC tumor cells. Using genetic (CRISPR-activation) and/or pharmacologic modulation, we functionally interrogate the CD155/TIGIT axis and demonstrate that increased signaling through CD155 and/or TIGIT is sufficient to promote immune evasion in neoantigen-expressing PDAC. Lastly, we identified a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in these preclinical models. Using a suite of high-resolution analyses, we are dissecting the mechanisms of effectiveness and resistance to this combination immunotherapy, which is set to enter clinical trials in pancreatic cancer later this year. Citation Format: William Freed-Pastor, Laurens Lambert, Zackery Ely, Nimisha Pattada, Arjun Bhutkar, Alex Jaeger, George Eng, Kim Mercer, William Hwang, Tyler Jacks. Functional interrogation of immune escape in neoantigen-expressing pancreatic cancer identifies a critical role for the CD155/TIGIT axis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-063.