Role of evaluating tumor‑infiltrating lymphocytes, programmed death‑1 ligand 1 and mismatch repair proteins expression in malignant mesothelioma

Losi,Lorena; Bertolini,Federica; Guaitoli,Giorgia; Fabbiani,Luca; Banchelli,Federico; Ambrosini‑Spaltro,Andrea; Botticelli,Laura; Scurani,Letizia; Baldessari,Cinzia; Barbieri,Fausto; Cascinu,Stefano; Maiorana,Antonino

doi:10.3892/ijo.2019.4883

Role of evaluating tumor‑infiltrating lymphocytes, programmed death‑1 ligand 1 and mismatch repair proteins expression in malignant mesothelioma

Authors:
- Lorena Losi
- Federica Bertolini
- Giorgia Guaitoli
- Luca Fabbiani
- Federico Banchelli
- Andrea Ambrosini‑Spaltro
- Laura Botticelli
- Letizia Scurani
- Cinzia Baldessari
- Fausto Barbieri
- Stefano Cascinu
- Antonino Maiorana
View Affiliations

Affiliations: Department of Life Sciences, University of Modena and Reggio Emilia, I‑41124 Modena, Italy, Division of Medical Oncology, Azienda Ospedaliero‑Universitaria Policlinico, I‑41124 Modena, Italy, Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, I‑41124 Modena, Italy, Unit of Pathology, Azienda Ospedaliero‑Universitaria Policlinico, I‑41124 Modena, Italy
Published online on: September 20, 2019 https://doi.org/10.3892/ijo.2019.4883
Pages: 1157-1164

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The tumor immune microenvironment (TME) and immune checkpoints have been reported to serve a role in the pathogenesis of malignant mesothelioma (MM) and treatment outcome. Additionally, mismatch Repair (MMR) deficiency appears to enhance the response to checkpoints blockade in several tumors. The aim of the present study was to analyze programmed death‑1 ligand 1 (PD‑L1) expression in MM and to characterize the TME. This could help to understand the immune response, and evaluate its prognostic and predictive values. We also investigated MMR protein expression. We retrospectively analyzed 55 mesotheliomas to determine PD‑L1, CD4+, CD8+, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2, mismatch repair system component (PMS2) expression. We used an immunoscore (1+, 2+ and 3+) to evaluate tumor‑infiltrating lymphocytes (TILs). TILs were observed in all but two samples (53/55); the majority had an immunoscore 1+ (30/53), while 2+/3+ was reported for 23/53 samples. A predominance of CD8+ was highlighted in 8 cases (15%). PD‑L1 expression of ≥1% on tumor cells was displayed in 40 cases; in 9 of these, ≥50% expression was reported. Of note, alterations in MMR staining was not observed. In addition, survival analysis revealed that epithelioid subtype was associated with better prognosis. We observed a trend towards poorer prognosis for ≥50% PD‑L1 expression on tumor cells, lower immunoscore (1+) and CD8+ TIL predominance. The present study highlighted the importance of exploring the TME and the standardization of PD‑L1 assessment guidelines to apply in the field of immunotherapy.

View Figures

View References

1	Merlo DF, Bruzzone M, Bruzzi P, Garrone E, Puntoni R, Maiorana L and Ceppi M: Mortality among workers exposed to asbestos at the shipyard of Genoa, Italy: A 55 years follow-up. Environ Health. 17:942018. View Article : Google Scholar : PubMed/NCBI
2	Ferrante D, Chellini E, Merler E, Pavone V, Silvestri S, Miligi L, Gorini G, Bressan V, Girardi P, Ancona L, et al: Italian pool of asbestos workers cohorts: Mortality trends of asbestos-related neoplasms after long time since first exposure. Occup Environ Med. 74:887–898. 2017. View Article : Google Scholar : PubMed/NCBI
3	Alley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B and van Brummelen E: Clinical safety and activity of pembrolizumab in patients with malignant pleural meso thelioma (KEYNOTE-028): Preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 18:623–630. 2017. View Article : Google Scholar : PubMed/NCBI
4	Travis WD, Brambilla E, Burke AP, Marx A and Nicholson AG: WHO classification of tumours of the Lung, Pleura, Thymus and Heart. WHO Press WHO Classification of Tumors. 7. 4th edition. Lyon; France: 2015
5	Hegmans JP, Hemmes A, Hammad H, Boon L, Hoogsteden HC and Lambrecht BN: Mesothelioma environment comprises cyto kines and T-regulatory cells that suppress immune responses. Eur Respir J. 27:1086–1095. 2006. View Article : Google Scholar : PubMed/NCBI
6	Anraku M, Cunningham KS, Yun Z, Tsao MS, Zhang L, Keshavjee S, Johnston MR and de Perrot M: Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 135:823–829. 2008. View Article : Google Scholar : PubMed/NCBI
7	Chen DS and Mellman I: Oncology meets immunology: The cancer-immunity cycle. Immunity. 39:1–10. 2013. View Article : Google Scholar : PubMed/NCBI
8	Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, et al: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regu lation of lymphocyte activation. J Exp Med. 192:1027–1034. 2000. View Article : Google Scholar : PubMed/NCBI
9	Keir ME, Francisco LM and Sharpe AH: PD-1 and its ligands in T-cell immunity. Curr Opin Immunol. 19:309–314. 2007. View Article : Google Scholar : PubMed/NCBI
10	Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK and Sharpe AH: PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 206:3015–3029. 2009. View Article : Google Scholar : PubMed/NCBI
11	Teng F, Meng X, Kong L and Yu J: Progress and challenges of predictive biomarkers of anti PD-1/PD-L1 immunotherapy: A systematic review. Cancer Lett. 414:166–173. 2018. View Article : Google Scholar
12	Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Files DB, Roche PC, Lu J, Zhu G, Tamada K, et al: Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med. 8:793–800. 2002. View Article : Google Scholar : PubMed/NCBI
13	Marcq E, Pauwels P, Van Meerbeeck JP and Smits EL: Targeting immune checkpoints: New opportunity for mesothelioma treat ment? Cancer Treat Rev. 41:914–924. 2015. View Article : Google Scholar : PubMed/NCBI
14	Hassan R, Thomas A, Patel MR, Nemunaitis JJ, Bennouna J, Powderly JD, Taylor MH, Dowlati A, Chen F, Leach J, et al: Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical activity, and PD-L1 expres sion. J Clin Oncol. 34(15 Suppl): S8503. 2016. View Article : Google Scholar
15	Marcq E, Siozopoulou V, de Waele J, van Audenaerde J, Zwaenepoel K, Santemans E, Heins N, Pauwels P, van Meerbeeck JP and Smits EL: Prognostic and predic tive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma. Oncoimmunology. 6:e12612412016. View Article : Google Scholar
16	Pasello G, Zago G, Lunardi F, Urso L, Kern I, Vlacic G, Grosso F, Mencoboni M, Ceresoli GL, Schiavon M, et al: Malignant pleural mesothelioma immune microenvironment and checkpoint expres sion: Correlation with clinical-pathological features and intratumor heterogeneity over time. Ann Oncol. 29:1258–1265. 2018. View Article : Google Scholar : PubMed/NCBI
17	Watanabe T, Okuda K, Murase T, Moriyama S, Haneda H, Kawano O, Yokota K, Sakane T, Oda R, Inagaki H and Nakanishi R: Four immunohistochemical assays to measure the PD-L1 expression in malignant pleural mesothelioma. Oncotarget. 9:20769–20780. 2018. View Article : Google Scholar : PubMed/NCBI
18	Mansfield AS, Roden AC, Peikert T, Sheinin YM, Harrington SM, Krco CJ, Dong H and Kwon EC: B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol. 9:1036–1040. 2014. View Article : Google Scholar : PubMed/NCBI
19	Cedrés S, Ponce Aix S, Zugazagoitia J, Sansano I, Enguita A, Navarro-Mendivii A, Martinez-Marti A, Martinez P and Felip E: Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM). PLoS One. 10:e01210712015. View Article : Google Scholar
20	Thapa B, Salcedo A, Lin X, Walkiewicz M, Murone C, Ameratunga M, Asadi K, Deb S, Barnett SA, Knight S, et al: The immune microenvironment, genome-wide copy number aberra tions, and survival in mesothelioma. J Thorac Oncol. 12:850–859. 2017. View Article : Google Scholar : PubMed/NCBI
21	Combaz-Lair C, Galateau-Sallé F, McLeer-Florin A, Le Stang N, David-Boudet L, Duruisseaux M, Ferretti GR, Brambilla E, Lebecque S and Lantuejoul S: Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas. Hum Pathol. 52:9–18. 2016. View Article : Google Scholar : PubMed/NCBI
22	Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, De Castro G Jr, Psyrri A, Baste Rotllan N, Neupane PC, Bratland A, et al: KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In: Presented at ESMO Congress; Munich. 2018
23	Minnema-Luiting J, Vroman H, Aerts J and Cornelissen R: Heterogeneity in immune cell content in malignant pleural mesothelioma. Int J Mol Sci. 19:–pii: E1041. 2018. View Article : Google Scholar : PubMed/NCBI
24	Baretti M and Le DT: DNA mismatch repair in cancer. Pharmacol Ther. 189:45–62. 2018. View Article : Google Scholar : PubMed/NCBI
25	Dudley JC, Lin MT, Le DT and Eshleman JR: Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 22:813–820. 2016. View Article : Google Scholar : PubMed/NCBI
26	Cohen R, Pellat A, Boussion H, Svrcek M, Lopez-Trabada D, Troudilloud I, Afchain P and André T: Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency. Bull Cancer. 106:137–142. 2019. View Article : Google Scholar
27	Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, et al: Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 357:409–413. 2017. View Article : Google Scholar : PubMed/NCBI
28	Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J, et al: Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9:342017. View Article : Google Scholar : PubMed/NCBI
29	Ponti G, Losi L, Martorana D, Priola M, Boni E, Pollio A, Neri TM and Seidenari S: Clinicopathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas. Hered Cancer Clin Pract. 9:62011. View Article : Google Scholar
30	Neuman T, London M, Kania-Almog J, Litvin A, Zohar Y, Fridel L, Sandbank J, Barshak I and Vainer GW: A harmonization study for the use of 22C3 PD-L1 immunohistochemical staining on ventana's platform. J Thorac Oncol. 11:1863–1868. 2016. View Article : Google Scholar : PubMed/NCBI
31	Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE 010): A randomised controlled trial. Lancet. 387:1540–1550. 2016. View Article : Google Scholar
32	Rusch VW, Chansky K, Nowak AK, Rice D, Kindler H, Gill RR and Travis WD: Malignant pleural mesothelioma. Amin B: AJCC Cancer staging Manual. 8th edition. Switzerland: Springer; pp. 457–468. 2017, View Article : Google Scholar
33	Taube JM: Unleashing the immune system: PD-1 and PD-Ls in the pre-treatment tumor microenvironment and correlation with response to PD-1/PD-L1 blockade. Oncoimmunology. 3:e9634132014. View Article : Google Scholar
34	Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, et al: Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 32:1020–1030. 2014. View Article : Google Scholar : PubMed/NCBI
35	Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwai C, Gubens M, Horn L, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 372:2018–2028. 2015. View Article : Google Scholar : PubMed/NCBI
36	Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al: Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 373:1627–1639. 2015. View Article : Google Scholar : PubMed/NCBI
37	Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 373:123–135. 2015. View Article : Google Scholar : PubMed/NCBI
38	Valmary Degano S, Colpart P, Villeneuve L, Monnien F, M'Hamndi L, Lang Averous G, Capovilla M, Bibeau F, Laverriere MH, Verriele-Beurrier V, et al: Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malig nant mesothelioma: A RENAPE study. Eur J Surg Oncol. 43:1915–1923. 2017. View Article : Google Scholar
39	Hamid O and Carvajal RD: Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy. Expert Opin Biol Ther. 13:847–861. 2013. View Article : Google Scholar : PubMed/NCBI
40	Mittal D, Gubin MM, Schreiber RD and Smyth MJ: New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape. Curr Opin Immunol. 27:16–25. 2014. View Article : Google Scholar : PubMed/NCBI
41	Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM and Busund LT: Prognostic effect of epithelial and stromal lymphocyte infiltration in non small cell lung cancer. Clin Cancer Res. 14:5220–5227. 2008. View Article : Google Scholar : PubMed/NCBI
42	Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, et al: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 313:1960–1964. 2006. View Article : Google Scholar : PubMed/NCBI
43	Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO and Green AR: Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 29:1949–1955. 2011. View Article : Google Scholar : PubMed/NCBI
44	Yamada N, Oizumi S, Kikuchi E, Shinagawa N, Konishi-Sakakibara J, Ishimine A, Aoe K, Gemba K, Kishimoto T, Torigoe T and Nishimura M: CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother. 59:1543–1549. 2010. View Article : Google Scholar : PubMed/NCBI
45	Burt BM, Rodig SJ, Tilleman TR, Elbardissi AW, Bueno R and Sugarbaker DJ: Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma. Cancer. 117:5234–5244. 2011. View Article : Google Scholar : PubMed/NCBI
46	Arulananda S, Thapa B, Walkiewicz M, Zapparoli GV, Williams DS, Dobrovic A and John T: Mismatch repair protein defects and microsatellite instability in malignant pleural meso thelioma. J Thorac Oncol. 13:1588–1594. 2018. View Article : Google Scholar : PubMed/NCBI