The immune microenvironment in vulvar (pre)cancer: review of literature and implications for immunotherapy

References

• Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstetrics Gynecol. 2006;20(2):207–225.
   PubMed Web of Science ®Google Scholar
• Judson PL, Habermann EB, Baxter NN, et al. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstetrics Gynecol. 2006;107(5):1018–1022.
   PubMed Web of Science ®Google Scholar
• Kurman RJ, Carcangiu ML, Herrington CS, et al. WHO classification of tumours of female reproductive organs. Lyon: International Agency for Research on Cancer; 2014. 172.
   Google Scholar
• Pilotti S, Donghi R, D’Amato L, et al. Papillomavirus, p53 alteration and primary carcinoma of the vulva. Eur J Cancer. 1993;29a(6):924–925.
   PubMed Web of Science ®Google Scholar
• van der Avoort IA, Shirango H, Hoevenaars BM, et al. Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways. Int J Gynecol Pathol. 2006;25(1):22–29.
   PubMed Web of Science ®Google Scholar
• Santos M, Landolfi S, Olivella A, et al. p16 overexpression identifies HPV-positive vulvar squamous cell carcinomas. Am J Surg Pathol. 2006;30(11):1347–1356.
   PubMed Web of Science ®Google Scholar
• Schuurman MS, van Den Einden LCG, Massuger LFAG, et al. Trends in incidence and survival of dutch women with vulvar squamous cell carcinoma. Eur J Cancer. 2013;49(18):3872–3880.
   PubMed Web of Science ®Google Scholar
• de Hullu JA, van der Zee AG. Surgery and radiotherapy in vulvar cancer. Crit Rev Oncol Hematol. 2006;60(1):38–58.
   PubMed Web of Science ®Google Scholar
• van de Nieuwenhof HP, van der Avoort IA, de Hullu JA. Review of squamous premalignant vulvar lesions. Crit Rev Oncol Hematol. 2008;68(2):131–156.
   PubMed Web of Science ®Google Scholar
• Kokka F, Singh N, Faruqi A, et al. Is differentiated vulval intraepithelial neoplasia the precursor lesion of human papillomavirus-negative vulval squamous cell carcinoma? Int J Gynecol Cancer. 2011;21(7):1297–1305.
   PubMed Web of Science ®Google Scholar
• Nooij LS, Ter Haar NT, Ruano D, et al. Genomic characterization of vulvar (pre)cancers identifies distinct molecular subtypes with prognostic significance. Clin Cancer Res. 2017;23(22):6781–6789.
   PubMed Web of Science ®Google Scholar
• Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1):a001008.
   PubMed Web of Science ®Google Scholar
• Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol. 2005;32(Suppl 1):S16–S24.
   PubMed Web of Science ®Google Scholar
• van Seters M, van Beurden M, de Craen AJM. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol. 2005;97(2):645–651.
   PubMed Web of Science ®Google Scholar
• Wakeham K, Kavanagh K, Cuschieri K, et al. HPV status and favourable outcome in vulvar squamous cancer. Int J Cancer. 2017;140(5):1134–1146.
   PubMed Web of Science ®Google Scholar
• Rasmussen CL, Sand FL, Hoffmann Frederiksen M, et al. Does HPV status influence survival after vulvar cancer? Int J Cancer. 2018;142(6):1158–1165.
   PubMed Web of Science ®Google Scholar
• Hinten F, Molijn A, Eckhardt L, et al. Vulvar cancer: two pathways with different localization and prognosis. Gynecol Oncol. 2018;149(2):310-317.
   PubMed Web of Science ®Google Scholar
• Fridman WH, Pagès F, Sautès-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.
   PubMed Web of Science ®Google Scholar
• van der Burg SH, Palefsky JM. Human immunodeficiency virus and human papilloma virus - why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful. J Transl Med. 2009;7:108.
   PubMed Web of Science ®Google Scholar
• Petry KU, Köchel H, Bode U, et al. Human papillomavirus is associated with the frequent detection of warty and basaloid high-grade neoplasia of the vulva and cervical neoplasia among immunocompromised women. Gynecol Oncol. 1996;60(1):30–34.
   PubMed Web of Science ®Google Scholar
• Jamieson DJ, Paramsothy P, Cu-Uvin S, et al. Vulvar, vaginal, and perianal intraepithelial neoplasia in women with or at risk for human immunodeficiency virus. Obstet Gynecol. 2006;107(5):1023–1028.
   PubMed Web of Science ®Google Scholar
• Coleman N, Birley HD, Renton AM, et al. Immunological events in regressing genital warts. Am J Clin Pathol. 1994;102(6):768–774.
   PubMed Web of Science ®Google Scholar
• Welters MJ, van der Logt P, van Den Eeden SJF, et al. Detection of human papillomavirus type 18 E6 and E7-specific CD4+ T-helper 1 immunity in relation to health versus disease. Int J Cancer. 2006;118(4):950–956.
   PubMed Web of Science ®Google Scholar
• de Jong A, van Poelgeest MIE, van der Hulst JM, et al. Human papillomavirus type 16-positive cervical cancer is associated with impaired CD4+ T-cell immunity against early antigens E2 and E6. Cancer Res. 2004;64(15):5449–5455.
   PubMed Web of Science ®Google Scholar
• Snijders PJ, Steenbergen RD, Top B, et al. Analysis of p53 status in tonsillar carcinomas associated with human papillomavirus. J Gen Virol. 1994;75((Pt 10)):2769–2775.
   PubMedGoogle Scholar
• Wansom D, Light E, Worden F, et al. Correlation of cellular immunity with human papillomavirus 16 status and outcome in patients with advanced oropharyngeal cancer. Arch Otolaryngol Head Neck Surg. 2010;136(12):1267–1273.
   PubMedGoogle Scholar
• Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.
   PubMed Web of Science ®Google Scholar
• Badoual C, Hans S, Rodriguez J, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006;12(2):465–472.
   PubMed Web of Science ®Google Scholar
• Welters MJP, Ma W, Santegoets SJ, et al. Intratumoral HPV16-specific T-cells constitute a type 1 oriented tumor microenvironment to improve survival in HPV16-driven oropharyngeal cancer. Clin Cancer Res. 2017;24(3):634-647.
   PubMed Web of Science ®Google Scholar
• Bhatia A, Burtness B. Human papillomavirus-associated oropharyngeal cancer: defining risk groups and clinical trials. J Clin Oncol. 2015;33(29):3243–3250.
   PubMed Web of Science ®Google Scholar
• Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol. 2015;33(29):3305–3313.
   PubMed Web of Science ®Google Scholar
• Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–1867.
   PubMed Web of Science ®Google Scholar
• Glisson B, Barrios CH, Kim TM, et al. 1136ONivolumab and ISA 101 HPV vaccine in incurable HPV-16+ cancer. Annals Oncol. 2017;28(suppl_5):mdx376.002-mdx376.002.
   Google Scholar
• Hagerling C, Casbon AJ, Werb Z. Balancing the innate immune system in tumor development. Trends Cell Biol. 2015;25(4):214–220.
   PubMed Web of Science ®Google Scholar
• Berraondo P, Minute L, Ajona D, et al. Innate immune mediators in cancer: between defense and resistance. Immunol Rev. 2016;274(1):290–306.
   PubMed Web of Science ®Google Scholar
• Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol. 2017;10(1):58.
   PubMed Web of Science ®Google Scholar
• de Vos van Steenwijk PJ, Ramwadhdoebe TH, Goedemans R, et al. Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma. Int J Cancer. 2013;133(12):2884–2894.
   PubMed Web of Science ®Google Scholar
• van der Sluis TC, Sluijter M, van Duikeren S, et al. Therapeutic peptide vaccine-induced CD8 T cells strongly modulate intratumoral macrophages required for tumor regression. Cancer Immunol Res. 2015;3(9):1042–1051.
   PubMed Web of Science ®Google Scholar
• Thoreau M, Penny HL, Tan K, et al. Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid cells at the tumor site. Oncotarget. 2015;6(29):27832–27846.
   PubMedGoogle Scholar
• van Esch EMG, van Poelgeest MIE, Kouwenberg S, et al. Expression of coinhibitory receptors on T cells in the microenvironment of usual vulvar intraepithelial neoplasia is related to proinflammatory effector T cells and an increased recurrence-free survival. Int J Cancer. 2015;136(4):E95–E106.
   PubMed Web of Science ®Google Scholar
• van Esch EM, van Poelgeest MIE, Trimbos JBMZ, et al. Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV-induced vulvar neoplasia. Int J Cancer. 2015;136(4):E85–E94.
   PubMed Web of Science ®Google Scholar
• Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–1022.
   PubMed Web of Science ®Google Scholar
• Fujii N, Shomori K, Shiomi T, et al. Cancer-associated fibroblasts and CD163-positive macrophages in oral squamous cell carcinoma: their clinicopathological and prognostic significance. J Oral Pathol Med. 2012;41(6):444–451.
   PubMed Web of Science ®Google Scholar
• Komohara Y, Ohnishi K, Kuratsu J, et al. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008;216(1):15–24.
   PubMed Web of Science ®Google Scholar
• Kurahara H, Shinchi H, Mataki Y, et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res. 2011;167(2):e211–e219.
   PubMed Web of Science ®Google Scholar
• Hecking T, Thiesler T, Schiller C, et al. Tumoral PD-L1 expression defines a subgroup of poor-prognosis vulvar carcinomas with non-viral etiology. Oncotarget. 2017;8(54):92890–92903.
   PubMedGoogle Scholar
• Farrell AM, Marren P, Dean D, et al. Lichen sclerosus: evidence that immunological changes occur at all levels of the skin. Br J Dermatol. 1999;140(6):1087–1092.
   PubMed Web of Science ®Google Scholar
• Rotsztejn H, Trznadel-Budzko E, Jesionek-Kupnicka D. Langerhans cells in vulvar lichen sclerosus and vulvar squamous cell carcinoma. Arch Immunol Ther Exp (Warsz). 2006;54(5):363–366.
   PubMed Web of Science ®Google Scholar
• van Seters M, Beckmann I, Heijmans-Antonissen C, et al. Disturbed patterns of immunocompetent cells in usual-type vulvar intraepithelial neoplasia. Cancer Res. 2008;68(16):6617–6622.
   PubMed Web of Science ®Google Scholar
• Mulvany NJ, Allen DG. Differentiated intraepithelial neoplasia of the vulva. Int J Gynecol Pathol. 2008;27(1):125–135.
   PubMed Web of Science ®Google Scholar
• Singh K, Yeo Y, Honest H, et al. Antigen processing and correlation with immunological response in vulval intraepithelial neoplasia–a study of CD1a, CD54 and LN3 expression. Gynecol Oncol. 2006;102(3):489–492.
   PubMed Web of Science ®Google Scholar
• Jiang B, Xue M. Correlation of E6 and E7 levels in high-risk HPV16 type cervical lesions with CCL20 and Langerhans cells. Genet Mol Res. 2015;14(3):10473–10481.
   PubMed Web of Science ®Google Scholar
• Raspollini MR, Baroni G, Taddei GL. Langerhans cells in lichen sclerosus of the vulva and lichen sclerosus evolving in vulvar squamous cell carcinoma. Histol Histopathol. 2009;24(3):331–336.
   PubMed Web of Science ®Google Scholar
• Scrimin F, Rustja S, Radillo O, et al. Vulvar lichen sclerosus: an immunologic study. Obstet Gynecol. 2000;95(1):147–150.
   PubMed Web of Science ®Google Scholar
• Pahne-Zeppenfeld J, Schröer N, Walch-Rückheim B, et al. Cervical cancer cell-derived interleukin-6 impairs CCR7-dependent migration of MMP-9-expressing dendritic cells. Int J Cancer. 2014;134(9):2061–2073.
   PubMed Web of Science ®Google Scholar
• Heusinkveld M, de Vos van Steenwijk PJ, Goedemans R, et al. M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. J Immunol. 2011;187(3):1157–1165.
   PubMed Web of Science ®Google Scholar
• Demoulin SA, Sevko A, Heide J, et al. Cervical (pre)neoplastic microenvironment promotes the emergence of tolerogenic dendritic cells via RANKL secretion. Oncoimmunology. 2015;4(6):e1008334.
   PubMed Web of Science ®Google Scholar
• Sznurkowski JJ, Żawrocki A, Emerich J, et al. Expression of indoleamine 2,3-dioxygenase predicts shorter survival in patients with vulvar squamous cell carcinoma (vSCC) not influencing on the recruitment of FOXP3-expressing regulatory T cells in cancer nests. Gynecol Oncol. 2011;122(2):307–312.
   PubMed Web of Science ®Google Scholar
• Puccetti P, Grohmann U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat Rev Immunol. 2007;7(10):817–823.
   PubMed Web of Science ®Google Scholar
• Lee WS, Lee S-M, Kim M-K, et al. The tryptophan metabolite 3-hydroxyanthranilic acid suppresses T cell responses by inhibiting dendritic cell activation. Int Immunopharmacol. 2013;17(3):721–726.
   PubMed Web of Science ®Google Scholar
• de Jong RA, Toppen NL, Ten Hoor KA, et al. Status of cellular immunity lacks prognostic significance in vulvar squamous carcinoma. Gynecol Oncol. 2012;125(1):186–193.
   PubMed Web of Science ®Google Scholar
• Jung AC, Guihard S, Krugell S, et al. CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis. Int J Cancer. 2013;132(2):E26–E36.
   PubMed Web of Science ®Google Scholar
• Nasman A, Romanitan M, Nordfors C, et al. Tumor infiltrating CD8+ and Foxp3+ lymphocytes correlate to clinical outcome and human papillomavirus (HPV) status in tonsillar cancer. PLoS One. 2012;7(6):e38711.
   PubMed Web of Science ®Google Scholar
• Sznurkowski JJ, Zawrocki A, Emerich J, et al. Prognostic significance of CD4+ and CD8+ T cell infiltration within cancer cell nests in vulvar squamous cell carcinoma. Int J Gynecol Cancer. 2011;21(4):717–721.
   PubMed Web of Science ®Google Scholar
• Sznurkowski JJ, Zawrocki A, Biernat W. Subtypes of cytotoxic lymphocytes and natural killer cells infiltrating cancer nests correlate with prognosis in patients with vulvar squamous cell carcinoma. Cancer Immunol Immunother. 2014;63(3):297–303.
   PubMed Web of Science ®Google Scholar
• van Esch EM, Tummers B, Baartmans V, et al. Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV-induced usual vulvar intraepithelial neoplasia and implications for immunotherapy. Int J Cancer. 2014;135(4):830–842.
   PubMed Web of Science ®Google Scholar
• van Esch EM, Dam MCI, Osse MEM, et al. Clinical characteristics associated with development of recurrence and progression in usual-type vulvar intraepithelial neoplasia. Int J Gynecol Cancer. 2013;23(8):1476–1483.
   PubMed Web of Science ®Google Scholar
• Talebian Yazdi M, van Riet S, van Schadewijk A, et al. The positive prognostic effect of stromal CD8+ tumor-infiltrating T cells is restrained by the expression of HLA-E in non-small cell lung carcinoma. Oncotarget. 2016;7(3):3477–3488.
   PubMed Web of Science ®Google Scholar
• Gooden M, Lampen M, Jordanova ES, et al. HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8(+) T lymphocytes. Proc Natl Acad Sci USA. 2011;108(26):10656–10661.
   PubMed Web of Science ®Google Scholar
• Terlou A, Santegoets LAM, van der Meijden WI, et al. An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155. J Invest Dermatol. 2012;132(3 Pt 1):658–666.
   PubMed Web of Science ®Google Scholar
• Regauer S. Immune dysregulation in lichen sclerosus. Eur J Cell Biol. 2005;84(2–3):273–277.
   PubMed Web of Science ®Google Scholar
• Ben-Hur H, Ashkenazi M, Huszar M, et al. Lymphoid elements and apoptosis-related proteins (Fas, Fas ligand, p53 and bcl-2) in lichen sclerosus and carcinoma of the vulva. Eur J Gynaecol Oncol. 2001;22(2):104–109.
   PubMed Web of Science ®Google Scholar
• Farrell AM, Dean D, Millard PR, et al. Cytokine alterations in lichen sclerosus: an immunohistochemical study. Br J Dermatol. 2006;155(5):931–940.
   PubMed Web of Science ®Google Scholar
• Hunger RE, Brönnimann M, Kappeler A, et al. Detection of perforin and granzyme B mRNA expressing cells in lichen sclerosus. Exp Dermatol. 2007;16(5):416–420.
   PubMed Web of Science ®Google Scholar
• Carlson JA, Grabowski R, Chichester P, et al. Comparative immunophenotypic study of lichen sclerosus: epidermotropic CD57+ lymphocytes are numerous–implications for pathogenesis. Am J Dermatopathol. 2000;22(1):7–16.
   PubMed Web of Science ®Google Scholar
• Gross T, Wagner A, Ugurel S, et al. Identification of TIA-1+ and granzyme B+ cytotoxic T cells in lichen sclerosus et atrophicus. Dermatology. 2001;202(3):198–202.
   PubMed Web of Science ®Google Scholar
• Wenzel J, Wiechert A, Merkel C, et al. IP10/CXCL10 - CXCR3 interaction: a potential self-recruiting mechanism for cytotoxic lymphocytes in lichen sclerosus et atrophicus. Acta Derm Venereol. 2007;87(2):112–117.
   PubMed Web of Science ®Google Scholar
• Regauer S, Reich O, Beham-Schmid C. Monoclonal gamma-T-cell receptor rearrangement in vulvar lichen sclerosus and squamous cell carcinomas. Am J Pathol. 2002;160(3):1035–1045.
   PubMed Web of Science ®Google Scholar
• Mannweiler S, Sygulla S, Beham-Schmid C, et al. Penile carcinogenesis in a low-incidence area: a clinicopathologic and molecular analysis of 115 invasive carcinomas with special emphasis on chronic inflammatory skin diseases. Am J Surg Pathol. 2011;35(7):998–1006.
   PubMed Web of Science ®Google Scholar
• Gaarenstroom K, Kenter GG, Trimbos JB, et al. Postoperative complications after vulvectomy and inguinofemoral lymphadenectomy using separate groin incisions. Int J Gynecol Cancer. 2003;13(4):522–527.
   Google Scholar
• Pepas L, Kaushik S, Bryant A, et al. Medical interventions for high-grade vulval intraepithelial neoplasia. Cochrane Database Syst Rev. 2015;8(8):CD007924.
   Google Scholar
• Adams S, Kozhaya L, Martiniuk F, et al. Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin Cancer Res. 2012;18(24):6748–6757.
   PubMed Web of Science ®Google Scholar
• Schon MP, Schon M. Imiquimod: mode of action. Br J Dermatol. 2007;157(Suppl 2):8–13.
   PubMed Web of Science ®Google Scholar
• Wenzel J, Uerlich M, Haller O, et al. Enhanced type I interferon signaling and recruitment of chemokine receptor CXCR3-expressing lymphocytes into the skin following treatment with the TLR7-agonist imiquimod. J Cutan Pathol. 2005;32(4):257–262.
   PubMed Web of Science ®Google Scholar
• Beutner KR, Geisse JK, Helman D, et al. Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol. 1999;41(6):1002–1007.
   PubMed Web of Science ®Google Scholar
• de Witte CJ, van de Sande AJM, van Beekhuizen HJ, et al. Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review. Gynecol Oncol. 2015;139(2):377–384.
   PubMed Web of Science ®Google Scholar
• Westermann C, Fischer A, Clad A. Treatment of vulvar intraepithelial neoplasia with topical 5% imiquimod cream. Int J Gynaecol Obstet. 2013;120(3):266–270.
   Google Scholar
• van Seters M, van Beurden M, Ten Kate FJW, et al. Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med. 2008;358(14):1465–1473.
   PubMed Web of Science ®Google Scholar
• van Poelgeest MI, van Seters M, van Beurden M, et al. Detection of human papillomavirus (HPV) 16-specific CD4+ T-cell immunity in patients with persistent HPV16-induced vulvar intraepithelial neoplasia in relation to clinical impact of imiquimod treatment. Clin Cancer Res. 2005;11(14):5273–5280.
   PubMed Web of Science ®Google Scholar
• Terlou A, van Seters M, Kleinjan A, et al. Imiquimod-induced clearance of HPV is associated with normalization of immune cell counts in usual type vulvar intraepithelial neoplasia. Int J Cancer. 2010;127(12):2831–2840.
   PubMed Web of Science ®Google Scholar
• Daayana S, Elkord E, Winters U, et al. Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia. Br J Cancer. 2010;102(7):1129–1136.
   PubMed Web of Science ®Google Scholar
• Winters U, Daayana S, Lear JT, et al. Clinical and immunologic results of a phase II trial of sequential imiquimod and photodynamic therapy for vulval intraepithelial neoplasia. Clin Cancer Res. 2008;14(16):5292–5299.
   PubMed Web of Science ®Google Scholar
• Urosevic M, Maier T, Benninghoff B, et al. Mechanisms underlying imiquimod-induced regression of basal cell carcinoma in vivo. Arch Dermatol. 2003;139(10):1325–1332.
   PubMed Web of Science ®Google Scholar
• Brown SB, Brown EA, Walker I. The present and future role of photodynamic therapy in cancer treatment. Lancet Oncol. 2004;5(8):497–508.
   PubMed Web of Science ®Google Scholar
• Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity. Nat Rev Cancer. 2006;6(7):535–545.
   PubMed Web of Science ®Google Scholar
• Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic therapy. J Natl Cancer Inst. 1998;90(12):889–905.
   PubMed Web of Science ®Google Scholar
• Abdel-Hady ES, Martin-Hirsch P, Duggan-Keen M, et al. Immunological and viral factors associated with the response of vulval intraepithelial neoplasia to photodynamic therapy. Cancer Res. 2001;61(1):192–196.
   PubMed Web of Science ®Google Scholar
• van der Burg SH, Arens R, Ossendorp F, et al. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer. 2016;16(4):219–233.
   PubMed Web of Science ®Google Scholar
• Welters MJ, Kenter GG, Piersma SJ, et al. Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res. 2008;14(1):178–187.
   PubMed Web of Science ®Google Scholar
• Kenter GG, Welters MJP, Valentijn ARPM, et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med. 2009;361(19):1838–1847.
   PubMed Web of Science ®Google Scholar
• Davidson EJ, Boswell CM, Sehr P, et al. Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. Cancer Res. 2003;63(18):6032–6041.
   PubMed Web of Science ®Google Scholar
• Kauppila S, Kotila V, Knuuti E, et al. The effect of topical pimecrolimus on inflammatory infiltrate in vulvar lichen sclerosus. Am J Obstet Gynecol. 2010;202(2):181.e1–184.e1.
   PubMed Web of Science ®Google Scholar
• Lee A, Bradford J, Fischer G. Long-term management of adult vulvar lichen sclerosus: a prospective cohort study of 507 women. JAMA Dermatol. 2015;151(10):1061–1067.
   PubMed Web of Science ®Google Scholar
• Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J Clin Invest. 2001;107(2):135–142.
   PubMed Web of Science ®Google Scholar
• Mattern J, Büchler MW, Herr I. Cell cycle arrest by glucocorticoids may protect normal tissue and solid tumors from cancer therapy. Cancer Biology & Therapy. 2007;6(9):1341–1350.
   Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.
   PubMed Web of Science ®Google Scholar
• van PoelgeestMIE, Welters MJ, Vermeij R, et al. Vaccination against oncoproteins of HPV16 for noninvasive vulvar/vaginal lesions: lesion clearance is related to the strength of the T-cell response. Clin Cancer Res. 2016;22(10):2342–2350.
   PubMed Web of Science ®Google Scholar
• Wang X, Teng F, Kong L, et al. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–5039.
   PubMed Web of Science ®Google Scholar
• Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol. 2015;23:32–38.
   PubMed Web of Science ®Google Scholar
• Verdegaal EME, van der Burg SH. The potential and challenges of exploiting the vast but dynamic neoepitope landscape for immunotherapy. Front Immunol. 2017;8:1113.
   PubMed Web of Science ®Google Scholar
• Ilyas S, Yang JC. Landscape of tumor antigens in T cell immunotherapy. J Immunol. 2015;195(11):5117–5122.
   PubMed Web of Science ®Google Scholar
• Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500–2501.
   PubMed Web of Science ®Google Scholar
• Lechner A, Schlößer H, Rothschild SI, et al. Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma. Oncotarget. 2017;8(27):44418–44433.
   PubMedGoogle Scholar
• Welters MJP, Ma W, Santegoets SJAM, et al. Intratumoral HPV16-specific T cells constitute a type I-oriented tumor microenvironment to improve survival in HPV16-driven oropharyngeal cancer. Clin Cancer Res. 2018;24(3):634–647.
   PubMed Web of Science ®Google Scholar
• Howitt BE, Sun HH, Roemer MGM, et al. Genetic basis for PD-L1 expression in squamous cell carcinomas of the cervix and vulva. JAMA Oncol. 2016;2(4):518–522.
   PubMed Web of Science ®Google Scholar
• Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–571.
   PubMed Web of Science ®Google Scholar
• Karim R, Jordanova ES, Piersma SJ, et al. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res. 2009;15(20):6341–6347.
   PubMed Web of Science ®Google Scholar
• Obeid JM, Erdag G, Smolkin ME, et al. PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: correlation with tumor-infiltrating immune cells and clinical outcome. Oncoimmunology. 2016;5(11):e1235107.
   PubMed Web of Science ®Google Scholar
• Heeren AM, Punt S, Bleeker MC, et al. Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix. Mod Pathol. 2016;29(7):753–763.
   PubMed Web of Science ®Google Scholar
• Yu GT, Bu -L-L, Huang C-F, et al. PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPalpha axis in HPV negative head and neck squamous cell carcinoma. Oncotarget. 2015;6(39):42067–42080.
   PubMedGoogle Scholar
• Ottenhof SR, Djajadiningrat RS, de Jong J, et al. Expression of programmed death ligand 1 in penile cancer is of prognostic value and associated with HPV status. J Urol. 2017;197(3 Pt 1):690–697.
   PubMed Web of Science ®Google Scholar
• Sznurkowski JJ, Żawrocki A, Sznurkowska K, et al. PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients. Oncotarget. 2017;8(52):89903–89912.
   PubMedGoogle Scholar
• van der Burg SH, Piersma SJ, de Jong A, et al. Association of cervical cancer with the presence of CD4+ regulatory T cells specific for human papillomavirus antigens. Proc Natl Acad Sci U S A. 2007;104(29):12087–12092.
   PubMed Web of Science ®Google Scholar
• Prendergast GC, Malachowski WP, DuHadaway JB, et al. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 2017;77(24):6795–6811.
   PubMed Web of Science ®Google Scholar
• Matheu MP, Othy S, Greenberg ML, et al. Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat Commun. 2015;6:6219.
   PubMed Web of Science ®Google Scholar
• Trietsch MD, Spaans VM, Ter Haar NT, et al. CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma. Gynecol Oncol. 2014;135(1):149–155.
   PubMed Web of Science ®Google Scholar
• Spaans VM, Trietsch MD, Crobach S, et al. Designing a high-throughput somatic mutation profiling panel specifically for gynaecological cancers. PLoS One. 2014;9(3):e93451.
   PubMed Web of Science ®Google Scholar
• Jung YS, Najy AJ, Huang W, et al. HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer. Oncotarget. 2017;8(31):51530–51541.
   PubMedGoogle Scholar
• Haratani K, Hayashi H, Tanaka T, et al. Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. Ann Oncol. 2017;28(7):1532–1539.
   PubMed Web of Science ®Google Scholar
• Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–128.
   PubMed Web of Science ®Google Scholar
• Hodge JW, Ardiani A, Farsaci B, et al. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol. 2012;39(3):323–339.
   PubMed Web of Science ®Google Scholar
• Stevanovic S, Pasetto A, Helman SR, et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017;356(6334):200–205.
   PubMed Web of Science ®Google Scholar
• van Poelgeest MI, Visconti VV, Aghai Z, et al. Potential use of lymph node-derived HPV-specific T cells for adoptive cell therapy of cervical cancer. Cancer Immunol Immunother. 2016;65(12):1451–1463.
   PubMed Web of Science ®Google Scholar