LAUSR

Summary The biological and functional heterogeneity between tumors—both across and within cancer types—poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell‐inflamed and non‐T‐cell‐inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co‐injecting tumor cell clones revealed the non‐T‐cell‐inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor‐cell‐intrinsic production of the chemokine CXCL1 as a determinant of the non‐T‐cell‐inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell‐intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy. Graphical Abstract Figure. No caption available. HighlightsGenerated a library of congenic pancreatic cancer cell clones derived from KPC miceEach tumor elicited unique immune infiltration correlating with therapeutic responseTumors lacking T cells exhibit different epigenetic and transcriptomic statusCXCL1 was increased in therapy‐resistant tumors that lacked T cell infiltration &NA; Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor‐cell‐intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors.