Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell–inflamed tumor microenvironment are not fully understood. We used an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment (TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified ephrin-A receptor 2 (EPHA2) as a candidate tumor-intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that prostaglandin endoperoxide synthase 2 (PTGS2), the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGF-β and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2/PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2/TGF-β/PTGS2 pathway inhibitors with antitumor immunotherapy and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.
Nune Markosyan, Jinyang Li, Yu H. Sun, Lee P. Richman, Jeffrey H. Lin, Fangxue Yan, Liz Quinones, Yogev Sela, Taiji Yamazoe, Naomi Gordon, John W. Tobias, Katelyn T. Byrne, Andrew J. Rech, Garret A. FitzGerald, Ben Z. Stanger, Robert H. Vonderheide
Submitter: Peng Zhong | firstname.lastname@example.org
Authors: Minxiao Chen, Peng Zhong
Renmin Hospital of Wuhan University, Wuhan 430060, PR China
Published August 16, 2019
We have read with interest in the research paper of Marksyan et al. concerning the impact of tumor intrinsic factors on immunotherapies(1). Immunotherapies, especially immune checkpoint blockade (ICB), have led to significant improvement of clinical care for cancer patients(2). However, patients with melanoma, lung adenocarcinoma, or kidney cancer have only 20%–40% response rate to ICB, and the majority of patients with these and other types of cancer remain refractory to ICB(2). Therefore, identify the determinants that can predict the right person who will respond to immunotherapy are very important. Recently, the major predictive markers for checkpoint inhibitor response have been identified, including high tumor mutational burden, CD8 infiltrates, and PD-L1 overexpression(3). As for tumor mutational burden, T cells distinguish tumor cells from normal self in large part through the presentation of neoantigens created by the mutanome. The more neoantigens, the better the chance of immune recognition. Hence, high tumor mutational burden correlates with favorable outcome after checkpoint inhibitor treatment(3). As for the CD8 infiltrates, the study found that the abundance of tumor-infiltrating activated CD8+ T cells predicted the sensitivity to immunotherapy. The exclusion of CD8+ T cells from the vicinity of cancer cells mediated by tumor microenvironment (TME), has long been observed and confirmed in various types of cancer, even in the presence of tumor-specific T cells(4). Therefore, it is reasonable to conclude that until this problem is circumvented, the full potential of other approaches to T cell-mediated tumor immunotherapy, such as augmenting the numbers and function of cancer-specific T cells, may not be realized. The microenvironment of tumors contains numerous cell types in addition to cancer cells, which include bone marrow-derived inflammatory cells, lymphocytes, blood vessels, fibroblastic cells, and the extracellular matrix composed of collagen and proteoglycans. Preclinical studies in mouse models of cancer have implicated that all these cells in TME have a role in the restriction of the accumulation of T cells in the vicinity of cancer cells(4). However, the detailed mechanism of how these cell types in TME promotes the exclusion of tumor-infiltrating activated CD8+ T cells is still unknown. The research findings from Marksyan et al’s work published in the recent issue of Journal of Clinical Investigation, uncovered the intrinsic molecular mechanism originated from tumor cells that contributed to the exclusion of tumor-infiltrating activated CD8+ T cells(1). In Marksyan’s paper, the authors found that there exist tumor intrinsic factors that influence the abundance of tumor-infiltrating CD8+ T cells in the pancreatic adenocarcinoma (PDA), which is also refractory to immunotherapy and excludes T cells from the TME. Through an unbiased screen, the authors identified ephrin-A receptor 2 (EPHA2), a member of the EPH family of receptor tyrosine kinases, as a candidate tumor-intrinsic driver of immunosuppression. The evidence supporting the role of EPHA2 is showed as followed: (1) the expression of ephrin-A receptor 2 (EPHA2), is negatively correlated with the degree of T cell infiltration in PDA; (2) Deletion of EphA2 in tumor cells resulted in an increase in T cell infiltration and conferred sensitivity to immunotherapy. (3) Mechanistically, they found that prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2, lies downstream of EPHA2 signaling through TGF-β; (4) both genetic deletion and pharmacological inhibition of PTGS2 can also reverse T cell exclusion and sensitized tumors to immunotherapy; These study demonstrated that EPHA2/PTGS2 signaling in tumor cells regulates tumor immune phenotypes; Blockage this pathway may augment the intratumoral presence of activated CD8+ T cells, which will synergize with immunotherapy and improving the clinical outcomes.
In conclusion, this study provides a basis for targeting immunosuppressive signals arising from the tumor cells as a sensitization strategy for successful immunotherapy, and targeting EPHA2 or PTGS2 may have therapeutic potential as an additional component in immunotherapy in PDA.
1. Markosyan N, Li J, Sun YH, Richman LP, Lin JH, Yan F, et al. Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2). The Journal of clinical investigation. 2019;130. 2. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of medicine. 2012;366(26):2443-54. 3. Subbiah V, and Kurzrock R. Challenging Standard-of-Care Paradigms in the Precision Oncology Era. Trends in cancer. 2018;4(2):101-9. 4. Joyce JA, and Fearon DT. T cell exclusion, immune privilege, and tumor microenvironment. Science (New York, NY). 2015;348(6230):74-80.