İsmail SAYGIN, Mustafa Emre ERCİN, Emel ÇAKIR

Investigation of the relationship between immune checkpoints and mismatch repair deficiency in recurrent and nonrecurrent glioblastoma

Background/aim: Microsatellite instability tests and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) in the immune checkpoint pathway are the tests that determine who will benefit from immune checkpoint inhibitor therapy. We aimed to show the expression of DNA mismatch repair proteins and PD-1/PD-L1 molecules that inhibit immune checkpoints, to explain the relationship between them, and to demonstrate their predictive role in recurrent and nonrecurrent glioblastoma. Materials and methods: We analyzed 27 recurrent and 47 nonrecurrent cases at our archive. We performed immunohistochemical analysis to determine expressions of PD-1, PD-L1, and mismatch repair proteins in glioblastoma. We evaluated the relationship between these two group and compared the results with the clinicopathological features. Results: The mean age of diagnosis was significantly lower in recurrent glioblastoma patients. Median survival was longer in this group. We found that PD-L1 expression was reduced in recurrent cases. Additionally, recurrent cases had a significantly higher rate of microsatellite instability. Loss of PMS2 was high in both group but was substantially higher in recurrent cases. Conclusion: The presence of microsatellite instability and low PD-L1 levels, which are among the causes of treatment resistance in glioblastoma, were found to be compatible with the literature in our study, with higher rates in recurrent cases. In recurrent cases with higher mutations and where immunotherapy resistance is expected less, low PD-L1 levels thought that different combinations with other immune checkpoint inhibitors can be tried as predictive and prognostic marker in GBM patients.Key words: Glioblastoma, mismatch repair, programmed cell death protein ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), microsatellite instability

PDF

___

1. Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro-Oncology 2017; 19 (5):1-88. doi: 10.1093/ neuonc/nox158
2. Krex D, Klink B, Hartmann C, Von Deimling A, Pietsch T et al. Long-term survival with glioblastoma multiforme. Brain 2007; 130 (10): 2596-2606. doi: 10.1093/brain/awm204
3. Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. Journal of the National Cancer Institute 1993; 85 (9): 704-710. doi: 10.1186/1471-2407-9-450
4. Zheng T, Cantor KP, Zhang Y, Chiu BC, Lynch CF. Risk of brain glioma not associated with cigarette smoking or use of other tobacco products in Iowa. Cancer Epidemiology, Biomarkers & Prevention 2001; 10 (4): 413-414.
5. Huncharek M, Kupelnick B, Wheeler L. Dietary cured meat and the risk of adult glioma: a meta-analysis of nine observational studies. Journal of Environmental Pathology, Toxicology and Oncology 2003; 22 (2): 129-137. doi: 10.1615/ JEnvPathToxOncol.v22.i2.60
6. Kleihues P, Schäuble B, Zur Hausen A, Estève J, Ohgaki H. Tumors associated with p53 germline mutations: a synopsis of 91 families. The American Journal of Pathology 1997; 150 (1): 1-13.
7. Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunology Research 2016; 4 (2): 124-135. doi: 10.1158/2326- 6066.CIR-15-0151
8. Kurz SC, Wen PY. Quo Vadis-do immunotherapies have a role in glioblastoma? Current Treatment Options in Neurology 2018; 20 (5): 14. doi: 10.1007/s11940-018-0499-0
9. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008; 322 (5899): 271-275. doi: 10.1126/ science.1160062
10. Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ et al. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clinical Cancer Research 2013; 19 (12): 3165-3175. doi: 10.1158/1078- 0432
11. Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discovery 2015; 6 (8): 827-837. doi: 10.1158/2159-8290
12. Chen RQ, Liu F, Qiu XY, Chen XQ. The Prognostic and therapeutic value of PD-L1 in glioma. Frontiers in Pharmacology 2019; 9: 1503. doi: 10.3389/fphar.2018.01503
13. Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro-Oncology 2015; 17 (8): 1064-1075. doi: 10.1093/neuonc/nou307
14. Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY et al. PDL1 expression and prognostic impact in glioblastoma. NeuroOncology 2016; 18 (2): 195-205. doi: 10.1093/neuonc/nov172
15. Preusser M, Berghoff AS, Wick W, Weller M. Clinical Neuropathology mini-review 6-2015: PD-L1: emerging biomarker in glioblastoma? Clinical Neuropathology 2015; 34 (6): 313-321. doi: 10.5414/NP300922
16. Zeng J, Zhang XK, Chen HD, Zhong ZH, Wu QL et al. Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas. Oncotarget 2016; 7 (8): 8944-8955. doi: 10.18632/oncotarget.6884
17. Xue S, Song G, Yu J. The prognostic significance of PD-L1 expression in patients with glioma: a meta-analysis. Scientific Reports 2017; 7 (1): 4231. doi: 10.1038/s41598-017-04023-x
18. Heynckes S, Gaebelein A, Haaker G, Grauvogel J, Franco P et al. Expression differences of programmed death ligand 1 in de-novo and recurrent glioblastoma multiforme. Oncotarget 2017; 8 (43): 74170-74177. doi: 10.18632/oncotarget.18819
19. Bouffet E, Larouche V, Campbell BB, Merico D, De Borja R et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. Journal of Clinical Oncology 2016; 34 (19): 2206-2211. doi: 10.1200/JCO.2016.66.6552
20. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counterinhibitory checkpoints. Cancer Discovery 2015; 5 (1): 43-51. doi: 10.1158/2159-8290
21. Adhikaree J, Moreno-Vicente J, Kaur AP, Jackson AM, Patel PM. Resistance mechanisms and barriers to successful immunotherapy for treating glioblastoma. Cells 2020; 9 (2): 263. doi: 10.3390/cells9020263
22. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Science Translational Medicine 2016; 8 (328): 328rv4. doi: 10.1126/scitranslmed. aad7118
23. Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z et al. AntiPD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. International Journal of Radiation Oncology Biology, Physics 2013; 86 (2): 343-349. doi: 10.1016/j.ijrobp.2012.12.025
24. Roth P, Valavanis A, Weller M. Long-term control and partial remission after initial pseudo progression of glioblastoma by anti-PD-1 treatment with nivolumab. Neuro-Oncology 2017; 19 (3): 454-456. doi: 10.1093/neuonc/now265
25. Simonelli M, Di Tommaso L, Baretti M, Santoro A. Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Immunotherapy 2016; 8 (12): 1363-1369. doi: 10.2217/imt-2016-0057
26. Tihan T, Barletta J, Parney I, Lamborn K, Sneed PK et al. Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?. Human Pathology 2006; 37 (3): 272-282. doi: 10.1016/j.humpath.2005.11.010
27. Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC et al. Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. International Journal of Cancer 2011; 129 (3): 659-670. doi: 10.1002/ ijc.26083
28. Collage of American pathologist (2018). Template for Reporting Results of DNA Mismatch Repair Testing in Patients Being Considered for Checkpoint Inhibitor Immunotherapy (online). Website: https://documents.cap.org/protocols/cpgeneral-dnamismatchrepair-18biomarker-1001.pdf [accessed 09.10.2020].
29. Wang Z, Zhang C, Liu X, Wang Z, Sun L et al. Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma. Oncoimmunology 2016; 5 (11): e1196310. doi: 10.1080/2162402X.2016.1196310
30. Miyazaki T, Ishikawa E, Matsuda M, Akutsu H, Osuka S et al. Assessment of PD-1 positive cells on initial and secondary resected tumor specimens of newly diagnosed glioblastoma and its implications on patient outcome. Journal of NeuroOncology 2017; 133 (2): 277-285. doi: 10.1007/s11060-017- 2451-7
31. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H et al. PD-1 blockade in tumors with mismatch-repair deficiency. The New England Journal of Medicine 2015; 372 (26): 2509-2520. doi: 10.1056/NEJMoa1500596
32. Leung SY, Chan TL, Chung LP, Chan AS, Fan YW et al. microsatellite instability and mutation of dna mismatch repair genes in gliomas. The American Journal of Pathology 1998; 153 (4): 1181-1188. doi: 10.1016/S0002-9440(10)65662-3
33. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science 2003; 348 (6230): 69-74. doi: 10.1126/ science.aaa4971
34. Martinez R, Schackert HK, Plaschke J, Baretton G, Appelt H et al. Molecular mechanisms associated with chromosomal and microsatellite instability in sporadic glioblastoma multiforme. Oncology 2004; 66: 395-403. doi: 10.1159/000079488
35. Hodges TR, Ott M, Xiu J, Gatalica Z, Swensen J et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro-Oncology 2017; 19 (8): 1047-1057. doi: 10.1093/neuonc/nox026
36. Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clinical Cancer Research 2007; 13 (7): 2038-2045. doi: 10.1158/1078-0432.CCR-06-2149
37. Shinsato Y, Furukawa T, Yunoue S, Yonezawa H, Minami K et al. Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma. Oncotarget 2013; 4 (12): 2261-2270. doi: 10.18632/ oncotarget.1302
38. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357 (6349): 409-413. doi: 10.1126/science.aan6733
39. Castro MP, Goldstein N. Mismatch repair deficiency associated with complete remission to combination programmed cell death ligand immune therapy in a patient with sporadic urothelial carcinoma: immunotheranostic considerations. Journal for Immunotherapy of Cancer 2015; 3: 58. doi: 10.1186/ s40425-015-0104-y
40. Yamashita H, Nakayama K, Ishikawa M, Nakamura K, Ishibashi T et al. Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer. Oncotarget 2018; 9 (5): 5652-5664. doi: 10.18632/oncotarget.23790