Top

Published in:

01-12-2020 | Human Papillomavirus | Original Article

Induction of systemic immune responses and reversion of immunosuppression in the tumor microenvironment by a therapeutic vaccine for cervical cancer

Authors: Yuxin Che, Yang Yang, Jinguo Suo, Yujing An, Xuelian Wang

Published in: Cancer Immunology, Immunotherapy | Issue 12/2020

Abstract

Cervical cancer is the most common malignant tumor of the genital tract in females worldwide. Persistent human papillomavirus (HPV) infection is closely associated with the occurrence of cervical cancer. No licensed therapeutic HPV vaccines for cervical cancer are currently available. In our previous study, we demonstrated that the vaccine containing the HPV16 E7 43-77 peptide and the adjuvant unmethylated cytosine-phosphate-guanosine oligodeoxynucleotide elicited significant prophylactic and therapeutic effects on cervical cancer. In the current study, we comprehensively evaluated the effect of the vaccine on systemic immune responses and the tumor microenvironment (TME) in a mouse model of cervical cancer. The results showed that the administration of the vaccine induced a significant increase in splenic IFN-γ-producing CD4 and CD8 T cells as well as tumor infiltrating CD4 and CD8 T cells. Moreover, marked decreases in splenic MDSCs and Tregs as well as intratumoral MDSCs, Tregs and type 2-polarized tumor-associated macrophages were observed in the vaccine group. The profile of cytokines, chemokines and matrix metalloproteinases (MMPs) in the TME revealed significantly increased expression of IL-2, IL-12, TNF-α, IFN-γ, CCL-20, CXCL-9, CXCL-10 and CXCL-14 and decreased expression of IL-6, IL-10, TGF-β, CCL-2, CCL-3, CCL-5, CXCL-8, MMP-2, MMP-9 and VEGF in the vaccine group. The expression of the cell proliferation indicator Ki67, apoptosis regulatory protein p53 and angiogenesis marker CD31 was significantly decreased in the vaccine group. In conclusion, the vaccine reversed tolerogenic systemic and local TME immunosuppression and induced robust antitumor immune responses, which resulted in the inhibition of established implanted tumors.

Available only for authorised users

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492CrossRefPubMed

Burd EM (2003) Human papillomavirus and cervical cancer. Clin Microbiol Rev 16(1):1–17. https://doi.org/10.1128/cmr.16.1.1-17.2003CrossRefPubMedPubMedCentral

Castellsague X (2008) Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol 110(3 Suppl 2):S4–7. https://doi.org/10.1016/j.ygyno.2008.07.045CrossRefPubMed

Kim HJ, Kim HJ (2017) Current status and future prospects for human papillomavirus vaccines. Arch Pharmacal Res 40(9):1050–1063. https://doi.org/10.1007/s12272-017-0952-8CrossRef

Wigle J, Coast E, Watson-Jones D (2013) Human papillomavirus (HPV) vaccine implementation in low and middle-income countries (LMICs): health system experiences and prospects. Vaccine 31(37):3811–3817. https://doi.org/10.1016/j.vaccine.2013.06.016CrossRefPubMedPubMedCentral

Hoppe-Seyler K, Bossler F, Braun JA, Herrmann AL, Hoppe-Seyler F (2018) The HPV E6/E7 oncogenes: key factors for viral carcinogenesis and therapeutic targets. Trends Microbiol 26(2):158–168. https://doi.org/10.1016/j.tim.2017.07.007CrossRefPubMed

Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, Offringa R, van der Burg SH, Melief CJ (2008) Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients shows low toxicity and robust immunogenicity. Clin Cancer Res 14(1):169–177. https://doi.org/10.1158/1078-0432.CCR-07-1881CrossRefPubMed

van Poelgeest MI, Welters MJ, van Esch EM, Stynenbosch LF, Kerpershoek G, van van Persijn van Meerten EL, van den Hende M, Lowik MJ, Berends-van der Meer DM, Fathers LM, Valentijn AR, Oostendorp J, Fleuren GJ, Melief CJ, Kenter GG, van der Burg SH (2013) HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial. J Transl Med 11:88. https://doi.org/10.1186/1479-5876-11-88CrossRefPubMedPubMedCentral

Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, van der Burg SH, Melief CJ (2009) Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. New Engl J Med 361(19):1838–1847. https://doi.org/10.1056/NEJMoa0810097CrossRefPubMed

10.

Yang Y, Che Y, Zhao Y, Wang X (2019) Prevention and treatment of cervical cancer by a single administration of human papillomavirus peptide vaccine with CpG oligodeoxynucleotides as an adjuvant in vivo. Int Immunopharmacol 69:279–288. https://doi.org/10.1016/j.intimp.2019.01.024CrossRefPubMed

11.

Nagarsheth N, Wicha MS, Zou W (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17(9):559–572. https://doi.org/10.1038/nri.2017.49CrossRefPubMedPubMedCentral

12.

van der Burg SH, Ressing ME, Kwappenberg KM, de Jong A, Straathof K, de Jong J, Geluk A, van Meijgaarden KE, Franken KL, Ottenhoff TH, Fleuren GJ, Kenter G, Melief CJ, Offringa R (2001) Natural T-helper immunity against human papillomavirus type 16 (HPV16) E7-derived peptide epitopes in patients with HPV16-positive cervical lesions: identification of 3 human leukocyte antigen class II-restricted epitopes. Int J Cancer 91(5):612–618. https://doi.org/10.1002/1097-0215(200002)9999:9999%3c:aid-ijc1119%3e3.0.co;2-cCrossRefPubMed

13.

Dosset M, Godet Y, Vauchy C, Beziaud L, Lone YC, Sedlik C, Liard C, Levionnois E, Clerc B, Sandoval F, Daguindau E, Wain-Hobson S, Tartour E, Langlade-Demoyen P, Borg C, Adotevi O (2012) Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor. Clin Cancer Res 18(22):6284–6295. https://doi.org/10.1158/1078-0432.CCR-12-0896CrossRefPubMed

14.

Kalathil SG, Thanavala Y (2016) High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy. CII 65(7):813–819. https://doi.org/10.1007/s00262-016-1810-0CrossRefPubMed

15.

Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174. https://doi.org/10.1038/nri2506CrossRefPubMedPubMedCentral

16.

Marvel D, Gabrilovich DI (2015) Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Investig 125(9):3356–3364. https://doi.org/10.1172/JCI80005CrossRefPubMedPubMedCentral

17.

Kumar V, Patel S, Tcyganov E, Gabrilovich DI (2016) The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol 37(3):208–220. https://doi.org/10.1016/j.it.2016.01.004CrossRefPubMedPubMedCentral

18.

Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225. https://doi.org/10.1038/nature10138CrossRefPubMedPubMedCentral

19.

Arina A, Schreiber K, Binder DC, Karrison TG, Liu RB, Schreiber H (2014) Adoptively transferred immune T cells eradicate established tumors despite cancer-induced immune suppression. J Immunol 192(3):1286–1293. https://doi.org/10.4049/jimmunol.1202498CrossRefPubMed

20.

Arina A, Bronte V (2015) Myeloid-derived suppressor cell impact on endogenous and adoptively transferred T cells. Curr Opin Immunol 33:120–125. https://doi.org/10.1016/j.coi.2015.02.006CrossRefPubMed

21.

Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570. https://doi.org/10.1126/science.1203486CrossRefPubMed

22.

Liang Y, Lu B, Zhao P, Lu W (2019) Increased circulating GrMyeloid-derived suppressor cells correlated with tumor burden and survival in locally advanced cervical cancer patient. J Cancer 10(6):1341–1348. https://doi.org/10.7150/jca.29647CrossRefPubMedPubMedCentral

23.

Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787. https://doi.org/10.1016/j.cell.2008.05.009CrossRefPubMed

24.

Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24(34):5373–5380. https://doi.org/10.1200/JCO.2006.05.9584CrossRefPubMed

25.

Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A (2003) CD4 + CD25 + regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98(5):1089–1099. https://doi.org/10.1002/cncr.11618CrossRefPubMed

26.

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949. https://doi.org/10.1038/nm1093CrossRefPubMed

27.

Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543. https://doi.org/10.1073/pnas.0509182102CrossRefPubMedPubMedCentral

28.

Wu MY, Kuo TY, Ho HN (2011) Tumor-infiltrating lymphocytes contain a higher proportion of FOXP3(+) T lymphocytes in cervical cancer. Journal of the Formosan Medical Association = Taiwan yi zhi 110 (9):580-586. https://doi.org/10.1016/j.jfma.2011.07.005

29.

Nishikawa H (2014) [Regulatory T cells in cancer immunotherapy]. [Rinsho ketsueki] The Japanese journal of clinical hematology 55 (10):2183-2189

30.

Elkord E, Alcantar-Orozco EM, Dovedi SJ, Tran DQ, Hawkins RE, Gilham DE (2010) T regulatory cells in cancer: recent advances and therapeutic potential. Exp Opin Biol Ther 10(11):1573–1586. https://doi.org/10.1517/14712598.2010.529126CrossRef

31.

Schmidt A, Oberle N, Krammer PH (2012) Molecular mechanisms of treg-mediated T cell suppression. Front Immunol 3:51. https://doi.org/10.3389/fimmu.2012.00051CrossRefPubMedPubMedCentral

32.

Sawa-Wejksza K, Kandefer-Szerszen M (2018) Tumor-associated macrophages as target for antitumor therapy. Arch Immunol Ther Exp 66(2):97–111. https://doi.org/10.1007/s00005-017-0480-8CrossRef

33.

van Dalen FJ, van Stevendaal M, Fennemann FL, Verdoes M, Ilina O (2018) Molecular repolarisation of tumour-associated macrophages. Molecules 24 (1). https://doi.org/10.3390/molecules24010009

34.

Hanprasertpong J, Tungsinmunkong K, Chichareon S, Wootipoom V, Geater A, Buhachat R, Boonyapipat S (2010) Correlation of p53 and Ki-67 (MIB-1) expressions with clinicopathological features and prognosis of early stage cervical squamous cell carcinomas. J Obstetr Gynaecol Res 36(3):572–580. https://doi.org/10.1111/j.1447-0756.2010.01227.xCrossRef

35.

Hahn WC, Weinberg RA (2002) Rules for making human tumor cells. New Engl J Med 347(20):1593–1603. https://doi.org/10.1056/NEJMra021902CrossRefPubMed

36.

Yang C, Zhang J, Ding M, Xu K, Li L, Mao L, Zheng J (2018) Ki67 targeted strategies for cancer therapy. Clin Transl Oncol 20(5):570–575. https://doi.org/10.1007/s12094-017-1774-3CrossRefPubMed

37.

Li LT, Jiang G, Chen Q, Zheng JN (2015) Ki67 is a promising molecular target in the diagnosis of cancer (review). Mol Med Rep 11(3):1566–1572. https://doi.org/10.3892/mmr.2014.2914CrossRefPubMed

38.

Garzetti GG, Ciavattini A, Lucarini G, Goteri G, de Nictolis M, Muzzioli M, Fabris N, Romanini C, Biagini G (1995) MIB 1 immunostaining in stage I squamous cervical carcinoma: relationship with natural killer cell activity. Gynecol Oncol 58(1):28–33. https://doi.org/10.1006/gyno.1995.1179CrossRefPubMed

39.

Ho DM, Hsu CY, Chiang H (2000) MIB-1 labeling index as a prognostic indicator for survival in patients with FIGO stage IB squamous cell carcinoma of the cervix. Gynecol Oncol 76(1):97–102. https://doi.org/10.1006/gyno.1999.5663CrossRefPubMed

40.

Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253(5015):49–53. https://doi.org/10.1126/science.1905840CrossRefPubMed

41.

Levine AJ, Momand J, Finlay CA (1991) The p53 tumour suppressor gene. Nature 351(6326):453–456. https://doi.org/10.1038/351453a0CrossRefPubMed

42.

Munger K, Scheffner M, Huibregtse JM, Howley PM (1992) Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products. Cancer Surv 12:197–217PubMed

43.

Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC (2013) Human papillomavirus and cervical cancer. Lancet 382(9895):889–899. https://doi.org/10.1016/S0140-6736(13)60022-7CrossRefPubMed

44.

Avall-Lundqvist EH, Silfversward C, Aspenblad U, Nilsson BR, Auer GU (1997) The impact of tumour angiogenesis, p53 overexpression and proliferative activity (MIB-1) on survival in squamous cervical carcinoma. Eur J Cancer 33(11):1799–1804. https://doi.org/10.1016/s0959-8049(97)00161-5CrossRefPubMed

45.

Huang LW, Chou YY, Chao SL, Chen TJ, Lee TT (2001) p53 and p21 expression in precancerous lesions and carcinomas of the uterine cervix: overexpression of p53 predicts poor disease outcome. Gynecol Oncol 83(2):348–354. https://doi.org/10.1006/gyno.2001.6397CrossRefPubMed

46.

Shiohara S, Shiozawa T, Miyamoto T, Feng YZ, Kashima H, Kurai M, Suzuki A, Konishi I (2005) Expression of cyclins, p53, and Ki-67 in cervical squamous cell carcinomas: overexpression of cyclin A is a poor prognostic factor in stage Ib and II disease. Virchows Archiv 446(6):626–633. https://doi.org/10.1007/s00428-005-1252-0CrossRefPubMed

47.

Dellas A, Moch H, Schultheiss E, Feichter G, Almendral AC, Gudat F, Torhorst J (1997) Angiogenesis in cervical neoplasia: microvessel quantitation in precancerous lesions and invasive carcinomas with clinicopathological correlations. Gynecol Oncol 67(1):27–33. https://doi.org/10.1006/gyno.1997.4835CrossRefPubMed

48.

Tomao F, Papa A, Rossi L, Zaccarelli E, Caruso D, Zoratto F, Panici PB, Tomao S (2014) Angiogenesis and antiangiogenic agents in cervical cancer. Oncotargets Ther 7

49.

Rahma OE, Hodi FS (2019) The Intersection between tumor angiogenesis and immune suppression. Clin Cancer Res 25(18):5449–5457. https://doi.org/10.1158/1078-0432.CCR-18-1543CrossRefPubMed

50.

Pan PY, Wang GX, Yin B, Ozao J, Ku T, Divino CM, Chen SH (2008) Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111(1):219–228. https://doi.org/10.1182/blood-2007-04-086835CrossRefPubMedPubMedCentral

51.

Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC (2004) Expansion of myeloid immune suppressor Gr+ CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6(4):409–421. https://doi.org/10.1016/j.ccr.2004.08.031CrossRefPubMed

52.

Rivera LB, Bergers G (2015) Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol 36(4):240–249. https://doi.org/10.1016/j.it.2015.02.005CrossRefPubMedPubMedCentral

53.

Pahler JC, Tazzyman S, Erez N, Chen YY, Murdoch C, Nozawa H, Lewis CE, Hanahan D (2008) Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 10(4):329–340. https://doi.org/10.1593/neo.07871CrossRefPubMedPubMedCentral

Title: Induction of systemic immune responses and reversion of immunosuppression in the tumor microenvironment by a therapeutic vaccine for cervical cancer
Authors: Yuxin Che
Yang Yang
Jinguo Suo
Yujing An
Xuelian Wang
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Keywords: Human Papillomavirus
Cervical Cancer
Cervical Cancer
Published in: Cancer Immunology, Immunotherapy / Issue 12/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02651-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 12/2020

Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer

Pretreatment body mass index and clinical outcomes in cancer patients following immune checkpoint inhibitors: a systematic review and meta-analysis

Variation in neutrophil to lymphocyte ratio (NLR) as predictor of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (mNSCLC) patients treated with nivolumab

Factors associated with ocular adverse event after immune checkpoint inhibitor treatment

Characterizing caspase-1 involvement during esophageal disease progression

Increased Th17 activation and gut microbiota diversity are associated with pembrolizumab-triggered tuberculosis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer