Abstract A28: Investigation of tumor-cell-intrinsic factors regulating immune infiltration and response to immunotherapy in pancreatic cancer
Authors: Li Jinyang , Byrne Katelyn T , Markosyan Nune , Yamazoe Taiji , Yan Fangxue , Chen Zeyu , Sun Yu H. , Lin Jeffrey , Sela Yogev , Norgard Robert J. , Yuan Salina , Merrell Allyson J. , Tobias John W. , Vonderheide Robert H. , Stanger Ben Z. 
Published: March 2020

Resistance to immunotherapy is one major problem of current clinical care for cancer patients. While T-cell abundance is essential for tumor responsiveness to immunotherapy, factors that dictate T-cell infiltration in tumor microenvironments are not fully understood. To understand the tumor cell-intrinsic factors underlying the heterogeneity of tumor immunity and sensitivity to immunotherapy, we established a new experimental system by generating a library of congenic pancreatic tumor cell clones from a genetic mouse model driven by mutant Kras and p53. These tumor cell clones robustly formed implanted tumors that recapitulated the T cell-inflamed and non-T cell-inflamed tumor microenvironments in human patients, associated with distinct patterns of infiltration by T cells and myeloid cells. We found that the non-T cell-inflamed phenotype was dominant over the T cell-inflamed phenotype in the local tumor microenvironment. Both quantitative and qualitative features, specifically expression of markers of prior TCR activation, of intratumoral CD8+ T cells predicted the response to immunotherapies. An integrated transcriptomic and epigenetic analysis revealed that tumor cell-intrinsic expression of the chemokine CXCL1 as a major determinant of the non-T cell-inflamed microenvironment, and ablation of tumor cell-intrinsic CXCL1 promoted T-cell infiltration and sensitivity to a combination of chemotherapies, CD40 agonist, and checkpoint blockades. Similarly, we identified tumor cell-intrinsic EPHA2 and PTGS2 as key regulators of immune infiltration and immunotherapy response in our experimental system. Ablation of tumor cell-intrinsic EPHA2 or PTGS2 enhanced T-cell infiltration and suppressed myeloid cell infiltration in implanted pancreatic tumors, and increased sensitivities of tumors to the combined immunotherapy. These results demonstrated that heterogeneity of tumor immune phenotypes is driven by tumor cell-intrinsic factors that can be manipulated to influence the outcome of immunotherapies. The observation that non-T cell-inflamed phenotype is dominant emphasized the importance of targeting mechanisms driving T-cell low phenotype for improving immunotherapy response.

Citation Format: Jinyang Li, Katelyn T Byrne, Nune Markosyan, Taiji Yamazoe, Fangxue Yan, Zeyu Chen, Yu H. Sun, Jeffrey Lin, Yogev Sela, Robert J. Norgard, Salina Yuan, Allyson J. Merrell, John W. Tobias, Robert H. Vonderheide, Ben Z. Stanger. Investigation of tumor-cell-intrinsic factors regulating immune infiltration and response to immunotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A28.