Expression of PD-L1 in Microsatellite Instability High Tumours: A Retrospective Study

Abstract

Introduction: Microsatellite Instability (MSI) is the hallmark of Lynch syndrome/Constitutional Mismatch Repair Deficiency (CMMRD) and is also found in many sporadic cancers like colorectal cancer, endometrial, gastric, small intestine, urothelial, central nervous system and sebaceous gland neoplasms. MSI is a predictive biomarker for immunotherapy and Immunohistochemistry (IHC) antibodies against four Mismatch Repair (MMR) proteins: MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6) and Postmeiotic Segregation increased 2 (PMS2) can identify the MSI status of the tumour. In addition to MSI, immune checkpoint programmed cell death protein 1 (PD-1) expression and its ligand PD-L1 are biomarkers that can predict response to immunotherapy. Considering this increasing interest to identify deficient MMR (dMMR) status in different cancers, authors have assessed the expression of PD-L1 and status of MSI in various cancer types. Aim: To evaluate the expression of PD-L1 in MSI-high status tumours. Materials and Methods: This retrospective cross-sectional study was done in the Department of Pathology, Panimalar Medical College Hospital and Research Institute for a period of six months from July 2022 to December 2022. A total of 151 cases were identified for the period of three years from January 2020 to December 2022. The slides and blocks were retrieved from the archives. Tumour sections from the paraffin embedded tissues were deparaffinised and antigen retrieval was done. IHC using four antibodies (MLH1, MH2, MSH6 and PMS2) was performed on these slides to assess the MSI status. The slides were reviewed and were further subjected to PD-L1 IHC. PD-L1 expression on tumour cells was compared with the MSI status of different cancer types. The p-value was calculated using t-test and p<0.5 was considered statistically significant. Statistical analysis was done using International Business Machines (IBM) Statistical Package for the Social Sciences (SPSS) software version 21.0. Results: A total of 151 cases were included in the present study. A positive nuclear stain for the four MMR proteins denote expression of wild type MMR proteins, hence MSI low status. A loss of nuclear expression denotes mutation of MMR proteins and hence MSI high (MSI-H) status. The MSI was high in nine out of 48 cases (18.75%) of colon cancer, three out of 15 cases (20%) of endometrial cancers, three out of 20 cases (15%) of gastric cancers. Rest were one out of sixteen cases of ovarian cancer, one out of two malignant melanoma and one out of three glioblastoma. Out of these, PD-L1 was positive in seven of the 18 MSI-H cases (38.88% of MSI-H cases). The MSI was low/stable in the remaining 133 cases. The p-value of significance was 0.03 (statistically significant). Conclusion: This study shows a significant association of MSI-H with PD-L1 expression in tumours. Further large scale studies can help in assessing the role of PD-L1 as an effective therapeutic biomarker in MSI-high status patients who can benefit from targeted therapy.

Keywords

• lynch syndrome
• microsatellite instability
• mismatch repair deficiency
• mismatch repair proteins