ABSTRACT
Mismatch repair protein deficiency (dMMR) is a favorable prognostic factor in colorectal cancer. It is also associated with aberrant expression of HLA class I molecules, which are required for cytotoxic T lymphocyte-mediated cancer immunotherapy. Because dMMR is frequently also found in endometrial cancers (ECs), we retrospectively investigated the expression of mismatch repair proteins and HLA class I molecules in 127 EC patients. In this study, EC patients being treated in our hospital were recruited from 2005 to 2009 and observed until December 2017. Lesion specimens were evaluated via immunohistochemistry for MSH6 and PMS2 (mismatch repair proteins) and HLA class I molecules. Expression of these molecules was statistically related to clinical and pathological factors and prognosis. dMMR was detected in 33 patients and did not correlate with the expression level of HLA class I molecules (P = 0.60). On the other hand, unexpectedly, multivariate analysis revealed that intact expression of HLA class I molecules was associated with p53 overexpression (P = 0.004). Neither dMMR nor decreased expression of HLA class I molecules were prognostic factors. These results are inconsistent with previous findings for colorectal cancer. A distinctive local tissue immune microenvironment would underlie the discrepancy in the results between EC and colorectal cancer.
Subject(s)
Biomarkers, Tumor/deficiency , Colorectal Neoplasms/genetics , Endometrial Neoplasms/genetics , Gene Expression Regulation, Neoplastic/immunology , Histocompatibility Antigens Class I/genetics , Adult , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , DNA Mismatch Repair , DNA-Binding Proteins/analysis , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Endometrial Neoplasms/immunology , Endometrial Neoplasms/mortality , Endometrial Neoplasms/surgery , Endometrium/pathology , Endometrium/surgery , Female , Follow-Up Studies , Humans , Hysterectomy , Immunohistochemistry , Middle Aged , Mismatch Repair Endonuclease PMS2/analysis , Mismatch Repair Endonuclease PMS2/deficiency , Mismatch Repair Endonuclease PMS2/genetics , Progression-Free Survival , Retrospective Studies , Salpingo-oophorectomy , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Tumor Suppressor Protein p53/geneticsABSTRACT
Accumulating evidence indicates that immune checkpoint inhibition-mediated cancer immunotherapies greatly improve the prognosis of certain types of cancer. This approach is now becoming a standard therapy, joining surgery, radiotherapy, and chemotherapy. Because the costs of antibody drugs are now a socioeconomic burden in many countries, an urgent need in cancer immunotherapy is the identification of relevant biomarkers that can predict therapy efficacy. Recent studies have reported that colorectal adenocarcinoma with hereditary or sporadic deficiency in mismatch repair (MMR) proteins has high antigenicity and that detection of these proteins could be a promising way to estimate clinical response. In this study of 135 patients with colorectal cancer, we used immunohistochemistry to investigate the correlation between deficiency in MMR proteins and expression of human leukocyte antigen (HLA) class I molecules, a prerequisite of cytotoxic T-cell-based immunotherapy. Interestingly, MMR protein deficiency was an independent risk factor for the impaired expression of HLA class I molecules (odds ratio (OR)=10.44, 95% confidence interval (CI)=3.15-34.62, p<0.001), suggesting the existence of a putative entity that we have named "adaptive immune escape". Moreover, our results might provide a potential novel biomarker for the selection of patients who would respond to cancer immunotherapies. At the same time, the results suggest that we have to overcome the impaired expression of HLA class I molecules to further improve the cure rate of cancer immunotherapies.