Abstract 7463: Chromosomal instability elicits anti-tumor immunity in pancreatic cancer

Abstract

Abstract Chromosomal instability (CIN) is a hallmark of solid cancers and an established driver of disease progression, therapy resistance, metastasis and on the whole poor patient outcome. Pancreatic cancer is particularly devastating, defined by dismal survival rates with many patients presenting with metastatic disease upon diagnosis, and 5-year survival only reaching ~10%. Despite recent efforts to improve prognosis for pancreatic cancer patients with immunotherapies alone and in combination with other therapeutics progress remains limited. Despite CIN’s established role as a driver of disease progression, we have made the paradoxical observation that chromosomally unstable, murine pancreatic cancer cells elicit an anti-tumor immune response. CIN was induced experimentally in a chromosomally stable, metastatic model of pancreatic cancer. Modeling metastatic dissemination by injection of cells into the tail vein of mice led to robust tumor formation in the lungs where CIN-low cells formed many small lesions while CIN-high cells formed fewer but larger tumors. We investigated if the tumors were infiltrated differentially by immune cells by immunofluorescence and found that CIN-high tumors were more readily infiltrated by effector T-cells. This observation motivated us to test immunotherapy response in CIN-low and CIN-high cells. Subcutaneously implanted tumor cells were treated with an immune checkpoint inhibitor and isotype control antibody which revealed that CIN-high cells responded to immunotherapy while CIN-low cells did not. To put forward potential mechanisms explaining CIN-driven anti-tumor immunity, we performed molecular analyses of CIN-low and CIN-high tumors. First, we found that inflammatory pathways were significantly up-regulated in CIN-high tumors compared with CIN-low tumors. These findings were validated by cytokine measurements and RNA in situ hybridization. To dissect inflammatory pathway activation mechanistically, we engineered CIN-high cells using CRISPR/Cas9 that were deficient for key inflammatory cytokines and transcription factors. These experiments suppressed cell-intrinsic and ligand-induced inflammation. Yet, we failed to determine singular cytokine expression as mediator of anti-tumor immunity. To rule out the contribution of ligand-induced inflammation in the tumor microenvironment, we probed immune checkpoint blockade in combination with antibodies blocking inflammatory ligand receptors in CIN-high cells. We found that immune checkpoint blockade was cancer cell-intrinsic and independent of blocking antibodies. In summary, our data implicates CIN as a determinant of therapeutic and genetic anti-tumor immunity in a preclinical model of pancreatic cancer. Citation Format: Daniel Bronder, Roshan K. Sriram, Mercedes Duran, Melody Di Bona, Sarina McElduff, Samuel F. Bakhoum. Chromosomal instability elicits anti-tumor immunity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7463.