Impact of mismatch-repair deficiency on the colorectal cancer immune microenvironment
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Yingyi Zhang1,*, Zhao Sun1,*, Xinxin Mao2, Huanwen Wu2, Fei Luo1, Xi Wu1, Liangrui Zhou2, Jing Qin1, Lin Zhao1 and Chunmei Bai1
1Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
2Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
*These authors have contributed equally to this work
Lin Zhao, email: [email protected]
Chunmei Bai, email: [email protected]
Keywords: colorectal cancer, dMMR, tumor immune microenvironment, PD-1/PD-L1
Received: November 30, 2016 Accepted: July 23, 2017 Published: August 14, 2017
Colorectal cancer patients respond inconsistently to immunotherapies, likely due to the immune microenvironments around their tumors. We analyzed the relationship between deficient mismatch repair (dMMR) and the colorectal cancer immune microenvironment to identify predictors of effective immunotherapy. Colorectal cancer patients (n=113) who had undergone surgical resection were divided into dMMR and proficient mismatch repair (pMMR) groups. The levels of immune checkpoint proteins, including programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), indoleamine 2,3 dioxygenase and CD8 were assessed immunohistochemically. The percentage of tumor-infiltrating lymphocytes strongly positive for PD-1 (score=3) was higher in the dMMR than pMMR group (79.3% vs. 41.7%; p=0.003). The groups showed similar tumor cell PD-L1 positivity rates (34.5% vs. 35.7%, p=0.905) and PD-L1 intensity levels on immune cell infiltrates (86.2% vs. 84.5%, p=0.964). However, when a cut-off value of 80% was used for PD-L1 positivity, the rate of PD-L1 positivity on immune cell infiltrates differed between the groups (51.7% vs. 22.6%, p=0.003). The rate of high indoleamine 2,3 dioxygenase expression was greater in the dMMR than pMMR group (55.2% vs. 36.9%, p=0.026). CD8+ T cells were elevated in the dMMR group in both compartments (p=0.017 for tumor-infiltrating lymphocytes and stroma; p=0.038 for invasive front). Thus the immune microenvironment of dMMR colorectal cancer differs from that of pMMR colorectal cancer.
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