Abstract
Purpose
Squamous cell carcinoma of the vulva (SQCV) is the fifth most common cancer in women and accounts for about 5% of all genital cancers in women. The PD-L1 signaling pathway is activated in many malignant neoplasms and its blockade enhances anti-cancer immunity. The aim of our study was to examine the protein expression of PD-L1 and PD-1 in squamous cell cancer of the vulva, its correlations with clinicopathologic features and prognostic value.
Methods
Patients with SQCV treated in one institution were used for the analyses. PD-L1 immunohistochemistry was performed on 4 µm-thick section of the respective FFPE tissue blocks using the 28-8 antibody. PD-L1 scoring was performed separately for tumour cells (TC) and tumour associated immune cells. DNA was extracted to determine HPV status. Kaplan–Meier estimates for disease-free-survival and overall-survival were calculated and compared by log-rank test.
Results
PD-L1 expression in tumour cells could be observed in 32.9% of the patients. The expression of PD-L1 in peritumoural immune cells was confirmed in 91.4% of the patients. A significant correlation between PD-L1 expression in tumour cells and tumour stage was detected (p = 0.007). PD-L1 expression was independent from HPV status. Using the log-rank test we could not prove any significant differences in disease-free survival (p = 0.434) and overall survival (p = 0.858). Regression analysis showed that nodal status is a predictive factor of survival (p < 0.001).
Conclusion
The present study showed that a relevant amount of patients with squamous cell cancer of the vulva express PD-L1 in both, tumour cells and tumour-associated immune cells. Furthermore, the significant correlation of PD-L1 expression in TCs with tumour stage indicated the clinical impact of PD-L1 expression during tumour development. These data indicate that SQCV might be amenable to immune checkpoint-inhibition and constitute a rational for the future clinical trials.
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References
Beller U, Quinn MA, Benedet JL, Creasman WT, Ngan HYS, Maisonneuve P, Pecorelli S, Odicino F, Heintz APM (2006) Carcinoma of the vulva. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet 95(Suppl 1):S7–S27. https://doi.org/10.1016/s0020-7292(06)60028-3
Bertucci F, Finetti P, Colpaert C, Mamessier E, Parizel M, Dirix L, Viens P, Birnbaum D, van Laere S (2015) PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget 6:13506–13519
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643
Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. https://doi.org/10.1056/NEJMoa1200694
Callea M, Albiges L, Gupta M, Cheng S-C, Genega EM, Fay AP, Song J, Carvo I, Bhatt RS, Atkins MB, Hodi FS, Choueiri TK, McDermott DF, Freeman GJ, Signoretti S (2015) Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol Res 3:1158–1164. https://doi.org/10.1158/2326-6066.CIR-15-0043
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu T-E, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Wrangle JM, Rodriguez-Abreu D, Borghaei H, Blumenschein GR, Villaruz LC, Havel L, Krejci J, Corral Jaime J, Chang H, Geese WJ, Bhagavatheeswaran P, Chen AC, Socinski MA (2017) First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376:2415–2426. https://doi.org/10.1056/NEJMoa1613493
Choschzick M, Gut A, Fink D (2018) PD-L1 receptor expression in vulvar carcinomas is HPV-independent. Virchows Arch. https://doi.org/10.1007/s00428-018-2364-7
Del Pino M, Rodriguez-Carunchio L, Ordi J (2013) Pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma. Histopathology 62:161–175. https://doi.org/10.1111/his.12034
Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369. https://doi.org/10.1038/70932
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800. https://doi.org/10.1038/nm730
Fan CA, Reader J, Roque DM (2018) Review of immune therapies targeting ovarian cancer. Curr Treat Options Oncol 19:74. https://doi.org/10.1007/s11864-018-0584-3
Gargano JW, Wilkinson EJ, Unger ER, Steinau M, Watson M, Huang Y, Copeland G, Cozen W, Goodman MT, Hopenhayn C, Lynch CF, Hernandez BY, Peters ES, Saber MS, Lyu CW, Sands LA, Saraiya M (2012) Prevalence of human papillomavirus types in invasive vulvar cancers and vulvar intraepithelial neoplasia 3 in the United States before vaccine introduction. J Low Genit Tract Dis 16:471–479. https://doi.org/10.1097/LGT.0b013e3182472947
Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 17:e542–e551. https://doi.org/10.1016/S1470-2045(16)30406-5
Gong J, Chehrazi-Raffle A, Reddi S, Salgia R (2018) Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 6:8. https://doi.org/10.1186/s40425-018-0316-z
Hampl M, Deckers-Figiel S, Hampl JA, Rein D, Bender HG (2008) New aspects of vulvar cancer: changes in localization and age of onset. Gynecol Oncol 109:340–345. https://doi.org/10.1016/j.ygyno.2008.01.041
Hellmann MD, Ciuleanu T-E, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O’Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378:2093–2104. https://doi.org/10.1056/NEJMoa1801946
Kim HS, Lee JY, Lim SH, Park K, Sun J-M, Ko YH, Baek C-H, Y-i Son, Jeong HS, Ahn YC, Lee M-Y, Hong M, Ahn M-J (2015) Association between PD-L1 and HPV status and the prognostic value of PD-L1 in oropharyngeal squamous cell carcinoma. Cancer Res Treat 48:527–536. https://doi.org/10.4143/crt.2015.249
Kowalewska M, Radziszewski J, Goryca K, Bujko M, Oczko-Wojciechowska M, Jarzab M, Siedlecki JA, Bidzinski M (2012) Estimation of groin recurrence risk in patients with squamous cell vulvar carcinoma by the assessment of marker gene expression in the lymph nodes. BMC Cancer 12:223. https://doi.org/10.1186/1471-2407-12-223
Kurman RJ (ed) (2014) WHO classification of tumours of female reproductive organs, vol 4, 4th edn. World Health Organization classification of tumours. IARC, Lyon
Mahner S, Prieske K, Grimm D, Trillsch F, Prieske S, von Amsberg G, Petersen C, Mueller V, Jaenicke F, Woelber L (2015) Systemic treatment of vulvar cancer. Expert Rev Anticancer Ther 15:629–637. https://doi.org/10.1586/14737140.2015.1037837
Malhotra J, Jabbour SK, Aisner J (2017) Current state of immunotherapy for non-small cell lung cancer. Transl Lung Cancer Res 6:196–211. https://doi.org/10.21037/tlcr.2017.03.01
Mazanet MM, Hughes CCW (2002) B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J Immunol 169:3581–3588
Merkelbach-Bruse S, Jakob C, Tietze L, Schröder W, Rath W, Füzesi L (1999) Consensus polymerase chain reaction and enzyme-linked immunosorbent assay for human papillomavirus detection and typing in cervical specimens. Diagn Mol Pathol 8:32–38
Multhoff G, Molls M, Radons J (2012) Chronic inflammation in cancer development. Front Immunol. https://doi.org/10.3389/fimmu.2011.00098
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, S-l Teng, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–562. https://doi.org/10.1038/nature13904
Qing Y, Li Q, Ren T, Xia W, Peng Y, Liu G-L, Luo H, Yang Y-X, Dai X-Y, Zhou S-F, Wang D (2015) Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Dev Ther 9:901–909. https://doi.org/10.2147/DDDT.S75152
Raju S, Joseph R, Sehgal S (2018) Review of checkpoint immunotherapy for the management of non-small cell lung cancer. Immunotargets Ther 7:63–75. https://doi.org/10.2147/ITT.S125070
Raspagliesi F, Hanozet F, Ditto A, Solima E, Zanaboni F, Vecchione F, Kusamura S (2006) Clinical and pathological prognostic factors in squamous cell carcinoma of the vulva. Gynecol Oncol 102:333–337. https://doi.org/10.1016/j.ygyno.2005.12.027
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128. https://doi.org/10.1126/science.aaa1348
Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, Plodkowski A, Long N, Sauter JL, Rekhtman N, Hollmann T, Schalper KA, Gainor JF, Shen R, Ni A, Arbour KC, Merghoub T, Wolchok J, Snyder A, Chaft JE, Kris MG, Rudin CM, Socci ND, Berger MF, Taylor BS, Zehir A, Solit DB, Arcila ME, Ladanyi M, Riely GJ, Schultz N, Hellmann MD (2018) Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 36:633–641. https://doi.org/10.1200/JCO.2017.75.3384
Roach C, Zhang N, Corigliano E, Jansson M, Toland G, Ponto G, Dolled-Filhart M, Emancipator K, Stanforth D, Kulangara K (2016) Development of a companion diagnostic PD-L1 immunohistochemistry assay for pembrolizumab therapy in non-small-cell lung cancer. Appl Immunohistochem Mol Morphol 24:392–397. https://doi.org/10.1097/PAI.0000000000000408
Saglam O, Conejo-Garcia J (2018) PD-1/PD-L1 immune checkpoint inhibitors in advanced cervical cancer. Integr Cancer Sci Ther. https://doi.org/10.15761/icst.1000272
Schmidt LH, Kümmel A, Görlich D, Mohr M, Bröckling S, Mikesch JH, Grünewald I, Marra A, Schultheis AM, Wardelmann E, Müller-Tidow C, Spieker T, Schliemann C, Berdel WE, Wiewrodt R, Hartmann W (2015) PD-1 and PD-L1 expression in NSCLC indicate a favorable prognosis in defined subgroups. PLoS One 10:e0136023. https://doi.org/10.1371/journal.pone.0136023
Schultheis AM, Scheel AH, Ozretić L, George J, Thomas RK, Hagemann T, Zander T, Wolf J, Buettner R (2015) PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer 51:421–426. https://doi.org/10.1016/j.ejca.2014.12.006
Sznurkowski JJ, Żawrocki A, Sznurkowska K, Pęksa R, Biernat W (2017) PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients. Oncotarget 8:89903–89912. https://doi.org/10.18632/oncotarget.20911
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020–1030. https://doi.org/10.1200/JCO.2013.53.0105
Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287. https://doi.org/10.1038/nrc.2016.36
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon R-A, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122–133. https://doi.org/10.1056/NEJMoa1302369
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AMS, CA und BH are supported by Roche Pharma AG and Kölner Krebsstiftung. JP was supported by the Else Kröner-Fresenius Stiftung (EKFS-2014-A06 and 2016 Kolleg.19). AHS and RB have participated in advisory boards for BMS, MSD and F. Hoffmann-La Roche AG, pharmaceutical division. FT declares that she has no conflict of interest. BM declares that he has no conflict of interest. CP declares that she has no conflict of interest. LMS declares that he has no conflict of interest. PM declares that he has no conflict of interest.
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Thangarajah, F., Morgenstern, B., Pahmeyer, C. et al. Clinical impact of PD-L1 and PD-1 expression in squamous cell cancer of the vulva. J Cancer Res Clin Oncol 145, 1651–1660 (2019). https://doi.org/10.1007/s00432-019-02915-1
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DOI: https://doi.org/10.1007/s00432-019-02915-1