{
  "abstract": "Background Despite recent advances in cancer treatment, only 20-40% of all patients respond to immunotherapy and efficacy varies highly by tumor type. 1 Tumors with high infiltration of canonically anti-tumoral immune cells tend to display increased sensitivity to treatment. However, those with higher infiltration of pro-tumoral immune cells are much less amenable to immunotherapy.2 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.3 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.Methods 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: 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. Each clonal line was implanted subcutaneously into immunocompetent congenic mice to control for extrinsic influences on the immune microenvironment. We performed bulk RNA-seq to assess the transcriptional mechanisms behind this immune heterogeneity.Results Overall abundance of immunosuppressive granulocytic myeloid-derived suppressor cells (gMDSC) is significantly higher in pancreatic-origin tumors while infiltration of T-cells is lower as compared to that of lung-origin tumors, despite controlling for engraftment site. Increased T-cell infiltration in pancreas-origin tumors is associated with slower tumor growth and response to immune checkpoint blockade (ICB) and is governed by differential expression of oncogenic Myc and gMDSC recruiting cytokine CXCL1. 3 However, this is not true in lung-origin tumors, suggesting alternative mechanisms controlling immune infiltration and evasion. Reanalysis of this data revealed that most of our ‘T-cell high’ tumors are surprisingly poorly immune infiltrated overall, regardless of origin. Yet, a unique lung-origin population of ‘true’ T-cell high tumors emerged, characterized by poor growth in vivo, better response to ICB, and upregulation of apoptosis and angiogenesis related pathways as compared to other lung and pancreas-origin counterparts.Conclusions These results suggest that there are indeed tissue-of-origin specific differences in immune contexture that 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.References Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707–723.Chowell D, Yoo S-K, Valero C, Pastore A, Krishna C, Lee M, Hoen D, Shi H, Kelly DW, Patel N, Makarov V, Ma X, Vuong L, Sabio EY, Weiss K, Kuo F, Lenz TL, Samstein RM, Riaz N, Adusumilli PS, Balachandran VP, Plitas G, Hakimi AA, Abdel-Wahab O, Shoushtari AN, Postow MA, Motzer RJ, Ladanyi M, Zehir A, Berger MF, Gönen M, Morris LGT, Weinhold N, Chan TA. Improved prediction of immune checkpoint blockade efficacy across multiple cancer types. Nat. Biotechnol. 2022;40:499–506.Li J, Byrne KT, Yan F, Yamazoe T, Chen Z, Baslan T, Richman LP, Lin J, Sun YH, Rech AJ, Balli D, Hay CA, Sela Y, Merrell AJ, Liudahl SM, Gordon N, Norgard RJ, Yuan S, Yu S, Chao T, Ye S, Eisinger-Mathason TSK, Faryabi RB, Tobias JW, Lowe S, Coussens LM, Wherry EJ, Vonderheide RH, Stanger BZ. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity. 2018;49:178-193.e7.",
  "authors": [
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Jane Xie"
    },
    {
      "affiliations": [
        "University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Ben Stanger"
    }
  ],
  "title": "748 Tissue-of-origin determines immune cell heterogeneity and response to therapy via unique tumor cell-intrinsic factors",
  "uid": "a54b9c2d-6c5c-5d9f-ab08-332b91611ffa"
}