Abstract A046: Tissue-of-origin determines immune cell heterogeneity and response to therapy via unique tumor cell-intrinsic factors

Abstract Despite recent advances in cancer treatment, only 20-40% of all patients respond to immunotherapy. Further, efficacy varies highly by tumor type. Tumors with high infiltration of canonically anti-tumoral immune cells, such as lung cancers, also tend to display increased sensitivity to treatment. In contrast, those with higher infiltration of pro-tumoral immune cells, such as pancreatic cancers, are much less amenable to immunotherapy. These differences in immune infiltration have been linked to differential transcriptional regulation of immune cell recruiting factors, suggesting that perhaps tumors can intrinsically assemble different immune microenvironments in a tissue-of-origin dependent manner. Thus, it is necessary to better understand the factors that lead to heterogeneity of immune cell infiltration, how these mechanisms differ across tumor types, and how they may be perturbed to improve therapy responses. Here, we utilized two panels of clonal cell lines both driven by Kras-G12D and Tp53-R172H mutations but derived from two different tissues of origin: the lung and pancreas. These panels serve to recapitulate the immune heterogeneity of non-small cell lung cancer and pancreatic ductal adenocarcinoma, respectively, while controlling for genetic drivers that may influence immune infiltration. Analyses of subcutaneously implanted lung and pancreatic-origin tumors revealed that the overall abundance of immunosuppressive granulocytic myeloid-derived suppressor cells (gMDSCs) is significantly higher in pancreatic-origin tumors while the infiltration of dendritic cells is much lower as compared to that of lung-origin tumors, despite controlling for engraftment site. Likewise, lung, but not pancreatic-origin tumors exhibit more rapid tumor growth upon natural killer (NK) cell depletion, suggesting a lung-origin specific role of NK cells in controlling tumor burden. There were also similarities in immune archetype, with T-cell abundance negatively correlating with that of gMDSCs. However, whereas “T-cell inflamed” pancreatic tumors partially respond to immune checkpoint blockade, their lung-origin counterparts do not. We hypothesized that these differences in immune phenotype and subsequent therapy response may be due in part to somatic copy number alterations (SCNAs). We performed sparse whole genome sequencing and identified substantial genomic rearrangements in both lung and pancreatic-origin tumors. Notably, the specific regions of rearrangements differed highly between the two panels, with lung-origin clones showing more amplifications in chromosomes 2 and 11 and deletions in chromosomes 16 and 18. These results suggest that there are indeed tissue-of-origin specific differences in immune phenotype that can influence therapy outcome. Ongoing work seeks to further elucidate specific tumor cell-intrinsic factors that can be leveraged to skew the tumor immune microenvironment towards a more anti-tumoral phenotype and ultimately increase sensitivity to immunotherapy in a site-specific manner. Citation Format: Jane Xie, Timour Baslan, Ben Stanger. Tissue-of-origin determines immune cell heterogeneity and response to therapy via unique tumor cell-intrinsic factors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A046.