Abstract 2912A: Intratumoral heterogeneity and immune checkpoint inhibitor response in the KPC pancreatic cancer model

Abstract

Cancer cells are subjected to evolutionary selection and adaptation of clonal populations by changes in the tumor and metastatic microenvironment as well as their response to drug treatment. We wished to evaluate how this tumor heterogeneity impacts the efficacy and responses to immune checkpoint blockade. To understand the contribution of clonal subpopulations to the malignant progression and to the response to drugs, we established a model of tumor heterogeneity from six syngeneic, clonal primary cancer cells isolated from a p48-CRE X LSLmutKras X LSLmutP53 mouse pancreatic cancer (KPC). The clonal cell lines were characterized for genomic mutations, gene expression and tumor allografts reconstituted in syngeneic host mice from mixes of the clonal cell lines. Each of the clonal cells formed invasive and metastatic lesions when grafted into hosts. The original tumor and clonal cell lines harbored common mutations in 99 genes demonstrating their common ancestry. Additional unique mutations in the clonal lines were used to identify and quantitate clones in heterogeneous cell pools. The clones showed different levels of MAP kinase signaling, unique morphologies, different growth rates in vitro and tumor growth rates in immune competent mice. Moreover, the sensitivity to ~200 anticancer drugs revealed an up to 25-fold varying in vitro sensitivity of the clones to signal transduction inhibitors and cytotoxic drugs. Drug sensitivity of individual clones when included in a heterogeneous cell population was strikingly different from their drug sensitivity when growing on their own including the sensitivity of different clones to MEK or PI3K inhibition. Furthermore, the sensitivity of clones to an anti-PD1 checkpoint inhibitor was distinct across the clonal cells growing in the heterogeneous mixture: Some clones were resistant and others highly sensitive to the checkpoint blockade. We will discuss pathways and drivers of resistance as well as sensitivity in the different subpopulations. We conclude that malignant progression and selection of checkpoint inhibitor sensitive cancer cell subpopulations is impacted by the crosstalk between clonal cell populations present in heterogeneous tumors and the host environment. Citation Format: Sarah Martinez Roth. Intratumoral heterogeneity and immune checkpoint inhibitor response in the KPC pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2912A.