ORIGINAL ARTICLE
Unravelling the link between mismatch repair protein deficiency and immune checkpoint markers – programmed death ligand 1 and galectin-9 expression in malignant melanoma
 
More details
Hide details
1
Karadeniz Technical University, Faculty of Medicine, Department of Pathology, Trabzon, Turkey
 
2
Lokman Hekim University, Department of Pathology, Ankara, Turkey
 
3
Koç University Hospital, Department of Dermatology, Istanbul, Turkey
 
4
Karadeniz Technical University, Faculty of Medicine, Department of Plastic and Reconstructive Surgery, Trabzon, Turkey
 
 
Submission date: 2024-12-18
 
 
Final revision date: 2025-09-14
 
 
Acceptance date: 2025-09-25
 
 
Publication date: 2025-11-05
 
 
Corresponding author
Gizem Teoman
Assistant Professor Dr. Gizem Teoman Department of Pathology Karadeniz Technical University Faculty of Medicine Trabzon, Turkey
 
 
Pol J Pathol 2025;76(3):239-247
 
KEYWORDS
TOPICS
ABSTRACT
Malignant melanoma is an aggressive skin cancer, with immune evasion mechanisms contributing to tumour progression. This study evaluated the relationship between mismatch repair (MMR) protein loss and the expression of immune checkpoint molecules programmed death ligand 1 (PD-L1) and galectin-9.
Ninety melanoma cases (60 primary, 30 metastatic) were analysed by immunohistochemistry for MMR proteins, PD-L1, and galectin-9. Associations with clinicopathological features and overall survival (OS) were assessed.
Mismatch repair protein loss occurred in 5% of primary and 16.7% of metastatic melanomas (p = 0.015). Programmed death ligand 1 was positive in 18.8% of cases, with higher expression in metastatic tumours, but this was not statistically significant (p = 0.106). All PD-L1 positive tumours retained MMR proteins. Galectin-9 expression tended to be higher in tumours with MMR loss and in PD-L1-positive cases, but correlations were not significant. Median OS was 26.0 months, and no variable significantly affected survival in multivariate analysis.
Mismatch repair loss was more frequent in metastatic melanomas and associated with higher galectin-9 expression, whereas PD-L1 showed no clear link with MMR status. None of the associations reached statistical significance, emphasising the descriptive and exploratory nature of the study.
These findings outline biomarker expression patterns in melanoma and support further investigation in larger cohorts, including patients treated with immune checkpoint inhibitors, to clarify their potential clinical relevance.
REFERENCES (21)
1.
Dzwierzynski WW. Managing malignant melanoma. Plast Reconstr Surg 2013; 132: 446e-60e.
 
2.
Rastrelli M, Tropea S, Rossi CR, Alaibac M. Melanoma: epidemiology, risk factors, pathogenesis, diagnosis, and classification. In Vivo 2014; 28: 1005-1011.
 
3.
Scolyer RA, Rawson RV, Gershenwald JE, Ferguson PM, Prieto VG. Melanoma pathology reporting and staging. Mod Pathol 2020; 33: 15-24.
 
4.
Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res 2016; 22: 813-820.
 
5.
Bhattacharya P, Patel TN. Microsatellite instability and promoter hypermethylation of DNA repair genes in hematologic Malignancies: a forthcoming direction toward diagnostics. Hematology 2018; 23: 77-82.
 
6.
Garcia JJ, Kramer MJ, O’Donnell RJ, Horvai AE. Mismatch repair protein expression and microsatellite instability: a comparison of clear cell sarcoma of soft parts and metastatic melanoma. Modern Pathology 2006; 19: 950-957.
 
7.
Ponti G, Longo C. Microsatellite instability and mismatch repair protein expression in sebaceous tumors, keratocanthoma, and basal cell carcinomas with sebaceous differentiation in Muir-Torre syndrome. J Am Acad Dermatol 2013; 68: 509-510.
 
8.
Shimozaki K, Hayashi H, Tanishima S, Horie S, Chida A, Tsugaru K, et al. Concordance analysis of microsatellite instability status between polymerase chain reaction based testing and next generation sequencing for solid tumors. Sci Rep 2021; 11: 20003.
 
9.
Nebot-Bral L, Coutzac C, Kannouche PL, Chaput N. Why is immunotherapy effective (or not) in patients with MSI/MMRD tumors? Bull Cancer 2019; 106: 105-113.
 
10.
Sunshine JC, Nguyen PL, Kaunitz GJ, Cottrell TR, Berry S, Esandrio J, et al. PD-L1 expression in melanoma: a quantitative immunohistochemical antibody comparison. Clin Cancer Res 2017; 23: 4938-4944.
 
11.
Zhang M, Liu C, Li Y, Li H, Zhang W, Liu J, et al. Galectin-9 in cancer therapy: from immune checkpoint ligand to promising therapeutic target. Front Cell Dev Biol 2023; 11: 1332205.
 
12.
Maule JG, Clinton LK, Graf RP, Xiao J, Oxnard GR, Ross JS, et al. Comparison of PD-L1 tumor cell expression with 22C3, 28-8, and SP142 IHC assays across multiple tumor types. J Immunother Cancer 2022; 10: e005573.
 
13.
Saygin I, Çakır E, Kazaz SN, Güvercin AR, Eyüboğlu İ, Ustaoğlu MM. Immunohistochemical analysis of the immune checkpoint molecule Galectin-9 in meningiomas. Cukurova Med J 2024; 49: 600-606.
 
14.
Mestrallet G, Brown M, Bozkus CC, Bhardwaj N. Immune escape and resistance to immunotherapy in mismatch repair deficient tumors. Front Immunol 2023; 14: 1210164.
 
15.
Russell BL, Sooklal SA, Malindisa ST, Daka LJ, Ntwasa M. The tumor microenvironment factors that promote resistance to immune checkpoint blockade therapy. Front Oncol 2021; 11: 641428.
 
16.
Diaz LA, Le DT. PD-1 blockade in tumors with mismatch- repair deficiency. N Engl J Med 2015; 372: 2509-2520.
 
17.
Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol 2017; 14: 463-482.
 
18.
Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun 2021; 12: 832.
 
19.
Díaz-García E, Alfaro E, Pérez-Moreno P, López-Fernández C, García-Sánchez A, Martínez-García MÁ, et al. Immune checkpoint biomarkers Galectin-9 and TIM-3 predict melanoma and lung cancer mortality in obstructive sleep apnoea. Arch Bronconeumol 2025; S0300-2896(25)00116-4.
 
20.
Enninga EA, Nevala WK, Holtan SG, Leontovich AA, Markovic SN. Galectin-9 modulates immunity by promoting Th2/M2 differentiation and impacts survival in patients with metastatic melanoma. Melanoma Res 2016; 26: 429-441.
 
21.
Wang L, Zhang C, Ji J, Jiao Q. Galectin-9: diverse roles in skin disease. Front Allergy 2025; 6: 1614277.
 
eISSN:2084-9869
ISSN:1233-9687
Journals System - logo
Scroll to top