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Review

Cervical Cancer: Emerging Immune Landscape and Treatment

& ORCID Icon
Pages 8037-8047 | Published online: 12 Aug 2020

References

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.2149230207593
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: Cancer J Clin. 2019;69(1):7–34. doi:10.3322/caac.2155130620402
  • Feng-Yi X, Feng X, Long S. Diagnostic accuracy of colposcopically directed biopsy and loop electrosurgical excision procedure for cervical lesions. Reprod Dev Med. 2018;2(3):137–141.
  • Qing W, Cai-Ying Z, Li-Mei C, et al. Clinical value of human papillomavirus E6/E7 mRNA testing in patients with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion. Reprod Dev Med. 2018;2(3):157–161.
  • Della Corte L, Barra F, Foreste V, et al. Advances in paclitaxel combinations for treating cervical cancer. Expert Opin Pharmacother. 2020;21(6):663–677. doi:10.1080/14656566.2020.172428432037907
  • Schwarz E, Freese UK, Gissmann L, et al. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature. 1985;314(6006):111–114. doi:10.1038/314111a02983228
  • Li S, Hong X, Wei Z, et al. Ubiquitination of the HPV oncoprotein E6 is critical for E6/E6AP-mediated p53 degradation. Front Microbiol. 2019;10:2483. doi:10.3389/fmicb.2019.0248331749782
  • Li Y, Xu C. Human papillomavirus-related cancers. Adv Exp Med Biol. 2017;1018:23–34.29052130
  • de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11(11):1048–1056. doi:10.1016/S1470-2045(10)70230-820952254
  • Schiffman M, Kjaer SK. Chapter 2: natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr. 2003;2003(31):14–19. doi:10.1093/oxfordjournals.jncimonographs.a003476
  • Liu L, Ying C, Zhao Z, et al. Identification of reliable biomarkers of human papillomavirus 16 methylation in cervical lesions based on integration status using high-resolution melting analysis. Clin Epigenetics. 2018;10:10. doi:10.1186/s13148-018-0445-829410710
  • Zhang R, Shen C, Zhao L, et al. Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV-related cervical carcinogenesis. Int J Cancer. 2016;138(5):1163–1174. doi:10.1002/ijc.2987226417997
  • Moscicki AB, Shiboski S, Hills NK, et al. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet. 2004;364(9446):1678–1683. doi:10.1016/S0140-6736(04)17354-615530628
  • Chun-Yan W, Yu-Qing Q, Yin-Yan H, Qing W, Xiao-Yong Z, Jun S. A retrospective review of 10 cases of villoglandular papillary adenocarcinoma of the uterine cervix including one with successful pregnancy. Reprod Dev Med. 2018;2(2):120–127.
  • Galliverti G, Wullschleger S, Tichet M, et al. Myeloid cells orchestrate systemic immunosuppression, impairing the efficacy of immunotherapy against HPV(+) cancers. Cancer Immunol Res. 2020;8(1):131–145. doi:10.1158/2326-6066.CIR-19-031531771984
  • Hirose S, Murakami N, Takahashi K, et al. Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients. Gynecol Oncol. 2020;156(1):203–210. doi:10.1016/j.ygyno.2019.10.02231757465
  • Hu Z, Zhu D, Wang W, et al. Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet. 2015;47(2):158–163. doi:10.1038/ng.317825581428
  • Chandimali N, Sun HN, Park YH, Kwon T. BRM270 suppresses cervical cancer stem cell characteristics and progression by inhibiting SOX2. In Vivo (Brooklyn). 2020;34(3):1085–1094. doi:10.21873/invivo.11879
  • Pan XB, Lu Y, Huang JL, Long Y, Yao DS. Prognostic genes in the tumor microenvironment in cervical squamous cell carcinoma. Aging (Albany NY). 2019;11(22):10154–10166. doi:10.18632/aging.10242931740624
  • Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16(1):1–17. doi:10.1128/CMR.16.1.1-17.200312525422
  • Shannon B, Yi TJ, Perusini S, et al. Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota. Mucosal Immunol. 2017;10(5):1310–1319. doi:10.1038/mi.2016.12928120845
  • Ivancic R, Iqbal H, deSilva B, Pan Q, Matrka L. Immunological tolerance of low-risk HPV in recurrent respiratory papillomatosis. Clin Exp Immunol. 2020;199(2):131–142. doi:10.1111/cei.1338731628850
  • Foy JP, Bertolus C, Michallet MC, et al. The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade. Ann Oncol. 2017;28(8):1934–1941. doi:10.1093/annonc/mdx21028460011
  • Huang H, Zhang M, Yao S, Zhang M, Peng J. Immune modulation of a lipid-soluble extract of Pinellia pedatisecta Schott in the tumor microenvironment of an HPV(+) tumor-burdened mouse model. J Ethnopharmacol. 2018;225:103–115. doi:10.1016/j.jep.2018.04.03729783020
  • Qiao G, Wang X, Zhou X, et al. Immune correlates of clinical benefit in a Phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors. Int J Hyperthermia. 2019;36(sup1):74–82. doi:10.1080/02656736.2019.164735031795830
  • Ma W, Wang K, Du J, Luan J, Lou G. Multi-dose parecoxib provides an immunoprotective effect by balancing T helper 1 (Th1), Th2, Th17 and regulatory T cytokines following laparoscopy in patients with cervical cancer. Mol Med Rep. 2015;11(4):2999–3008. doi:10.3892/mmr.2014.300325434365
  • Lv Q, Wu K, Liu F, Wu W, Chen Y, Zhang W. Interleukin17A and heparanase promote angiogenesis and cell proliferation and invasion in cervical cancer. Int J Oncol. 2018;53(4):1809–1817. doi:10.3892/ijo.2018.450330066843
  • Li T, Li M, Xu C, et al. miR146a regulates the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NFkappaB signaling by targeting TRAF6. Oncol Rep. 2019;41(5):2897–2908. doi:10.3892/or.2019.704630864722
  • Zhang Y, Wang ZC, Zhang ZS, Chen F. MicroRNA-155 regulates cervical cancer via inducing Th17/Treg imbalance. Eur Rev Med Pharmacol Sci. 2018;22(12):3719–3726. doi:10.26355/eurrev_201806_1525129949145
  • Zhang Y, Ma D, Zhang Y, et al. The imbalance of Th17/Treg in patients with uterine cervical cancer. Clin Chim Acta. 2011;412(11–12):894–900. doi:10.1016/j.cca.2011.01.01521255562
  • Chauhan SR, Singhal PG, Sharma U, Bandil K, Chakraborty K, Bharadwaj M. Th9 cytokines curb cervical cancer progression and immune evasion. Hum Immunol. 2019;80(12):1020–1025. doi:10.1016/j.humimm.2019.09.00931563404
  • Tuve S, Chen BM, Liu Y, et al. Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses. Cancer Res. 2007;67(12):5929–5939. doi:10.1158/0008-5472.CAN-06-429617575163
  • Bloom DD, Reshetylo S, Nytes C, Goodsett CT, Hematti P. Blockade of BAFF receptor BR3 on T cells enhances their activation and cytotoxicity. J Immunother. 2018;41(5):213–223. doi:10.1097/CJI.000000000000020929309290
  • Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179. doi:10.1038/srep1517926462617
  • Scott ME, Ma Y, Kuzmich L, Moscicki AB. Diminished IFN-gamma and IL-10 and elevated Foxp3 mRNA expression in the cervix are associated with CIN 2 or 3. Int J Cancer. 2009;124(6):1379–1383. doi:10.1002/ijc.2411719089920
  • Zeng C, Yao Y, Jie W, et al. Up-regulation of Foxp3 participates in progression of cervical cancer. Cancer Immunol Immunother. 2013;62(3):481–487. doi:10.1007/s00262-012-1348-822986453
  • Chen R, Gong Y, Zou D, Wang L, Yuan L, Zhou Q. Correlation between subsets of tumor-infiltrating immune cells and risk stratification in patients with cervical cancer. PeerJ. 2019;7:e7804. doi:10.7717/peerj.780431616592
  • Yang H, Ye S, Goswami S, et al. Highly immunosuppressive HLADR(hi) regulatory T cells are associated with unfavorable outcomes in cervical squamous cell carcinoma. Int J Cancer. 2019;146(7):1993–2006.31709528
  • Tian Y, Yuan C, Ma D, et al. IL-21 and IL-12 inhibit differentiation of Treg and TH17 cells and enhance cytotoxicity of peripheral blood mononuclear cells in patients with cervical cancer. Int J Gynecol Cancer. 2011;21(9):1672–1678. doi:10.1097/IGC.0b013e318235895522080897
  • Yin W, Duluc D, Joo H, et al. Therapeutic HPV cancer vaccine targeted to CD40 elicits effective CD8+ T-cell immunity. Cancer Immunol Res. 2016;4(10):823–834. doi:10.1158/2326-6066.CIR-16-012827485136
  • Maskey N, Thapa N, Maharjan M, et al. Infiltrating CD4 and CD8 lymphocytes in HPV infected uterine cervical milieu. Cancer Manag Res. 2019;11:7647–7655. doi:10.2147/CMAR.S21726431616181
  • Heeren AM, van Luijk IF, Lakeman J, et al. Neoadjuvant cisplatin and paclitaxel modulate tumor-infiltrating T cells in patients with cervical cancer. Cancer Immunol Immunother. 2019;68(11):1759–1767. doi:10.1007/s00262-019-02412-x31616965
  • 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. doi:10.1002/ijc.2830923740735
  • Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577(7791):561–565. doi:10.1038/s41586-019-1914-831942071
  • Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577(7791):549–555. doi:10.1038/s41586-019-1922-831942075
  • Petitprez F, de Reynies A, Keung EZ, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020;577(7791):556–560. doi:10.1038/s41586-019-1906-831942077
  • Kietlińska Z. T and B lymphocyte counts and blast transformation in patients with Stage I cervical cancer. Gynecol Oncol. 1984;18(2):247–256. doi:10.1016/0090-8258(84)90033-76610605
  • Tang A, Dadaglio G, Oberkampf M, et al. B cells promote tumor progression in a mouse model of HPV-mediated cervical cancer. Int J Cancer. 2016;139(6):1358–1371. doi:10.1002/ijc.3016927130719
  • Chen Z, Zhu Y, Du R, et al. Role of regulatory B cells in the progression of cervical cancer. Mediators Inflamm. 2019;2019:6519427. doi:10.1155/2019/651942731316301
  • Kim SS, Shen S, Miyauchi S, et al. B cells improve overall survival in HPV-associated squamous cell carcinomas and are activated by radiation and PD-1 blockade. Clin Cancer Res. 2020;26(13):3345–3359. doi:10.1158/1078-0432.CCR-19-321132193227
  • Lucena AA, Guimaraes MV, Michelin MA, et al. Evaluation of T, B and natural killer lymphocyte in the cervical stroma of HIV-positive and negative patients with cervical intraepithelial neoplasia. Immunol Lett. 2016;169:98–103. doi:10.1016/j.imlet.2015.10.01626545568
  • Cao G, Cui R, Liu C, Zhang G, Zhang Z. MTBHsp70-exFPR1-pulsed dendritic cells enhance the immune response against cervical cancer. J Cancer. 2019;10(25):6364–6373. doi:10.7150/jca.2977931772669
  • Wang Y, Huang H, Yao S, et al. A lipid-soluble extract of Pinellia pedatisecta Schott enhances antitumor T cell responses by restoring tumor-associated dendritic cell activation and maturation. J Ethnopharmacol. 2019;241:111980. doi:10.1016/j.jep.2019.11198031146000
  • Demoulin SA, Somja J, Duray A, et al. Cervical (pre)neoplastic microenvironment promotes the emergence of tolerogenic dendritic cells via RANKL secretion. Oncoimmunology. 2015;4(6):e1008334. doi:10.1080/2162402X.2015.100833426155412
  • Strickler HD, Martinson J, Desai S, et al. The relation of plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) with HPV persistence in HIV-infected and HIV-uninfected women. Viral Immunol. 2014;27(1):20–25. doi:10.1089/vim.2013.009724494969
  • Zhang B, Wei CY, Chang KK, et al. TSLP promotes angiogenesis of human umbilical vein endothelial cells by strengthening the crosstalk between cervical cancer cells and eosinophils. Oncol Lett. 2017;14(6):7483–7488. doi:10.3892/ol.2017.712129344192
  • Zhou WJ, Yang HL, Chang KK, et al. Human thymic stromal lymphopoietin promotes the proliferation and invasion of cervical cancer cells by downregulating microRNA-132 expression. Oncol Lett. 2017;14(6):7910–7916. doi:10.3892/ol.2017.726029250181
  • Xie F, Liu LB, Shang WQ, et al. The infiltration and functional regulation of eosinophils induced by TSLP promote the proliferation of cervical cancer cell. Cancer Lett. 2015;364(2):106–117. doi:10.1016/j.canlet.2015.04.02925979231
  • Holub K, Biete A. Impact of systemic inflammation biomarkers on the survival outcomes of cervical cancer patients. Clin Transl Oncol. 2019;21(7):836–844. doi:10.1007/s12094-018-1991-430470994
  • Zhu J, Wang H, Gao MJ, et al. Prognostic values of lymphocyte and eosinophil counts in resectable cervical squamous cell carcinoma. Future Oncol. 2019;15(30):3467–3481. doi:10.2217/fon-2018-087931580723
  • Zhu SY, Wu QY, Zhang CX, et al. miR-20a inhibits the killing effect of natural killer cells to cervical cancer cells by downregulating RUNX1. Biochem Biophys Res Commun. 2018;505(1):309–316. doi:10.1016/j.bbrc.2018.09.10230249397
  • Espinoza JL, Nguyen VH, Ichimura H, et al. A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to human papilloma virus-related cancers. Sci Rep. 2016;6:39231. doi:10.1038/srep3923127995954
  • Escarra-Senmarti M, Bueno-Topete MR, Jave-Suarez LF, et al. Loss of CD28 within CD4(+) T cell subsets from cervical cancer patients is accompanied by the acquisition of intracellular perforin, and is further enhanced by NKG2D expression. Immunol Lett. 2017;182:30–38. doi:10.1016/j.imlet.2017.01.00628087292
  • Chang WC, Li CH, Chu LH, Huang PS, Sheu BC, Huang SC. Regulatory T Cells Suppress Natural Killer Cell Immunity in Patients With Human Cervical Carcinoma. Int J Gynecol Cancer. 2016;26(1):156–162. doi:10.1097/IGC.000000000000057826512789
  • Saraswati W, Dahlan EG, Saputra K, Sutrisno TC. Effect of electroacupuncture on natural-killer cells and tumor size in patients with cervical squamous-cell carcinoma: a randomized controlled trial. Med Acupunct. 2019;31(1):29–36. doi:10.1089/acu.2018.131630805077
  • Wang J, Li Z, Gao A, Wen Q, Sun Y. The prognostic landscape of tumor-infiltrating immune cells in cervical cancer. Biomed Pharmacother. 2019;120:109444. doi:10.1016/j.biopha.2019.10944431562978
  • Pedraza-Brindis EJ, Sanchez-Reyes K, Hernandez-Flores G, et al. Culture supernatants of cervical cancer cells induce an M2 phenotypic profile in THP-1 macrophages. Cell Immunol. 2016;310:42–52. doi:10.1016/j.cellimm.2016.07.00127502363
  • Li Y, Huang G, Zhang S. Associations between intratumoral and peritumoral M2 macrophage counts and cervical squamous cell carcinoma invasion patterns. Int J Gynaecol Obstet. 2017;139(3):346–351. doi:10.1002/ijgo.1232028884821
  • Hammes LS, Tekmal RR, Naud P, et al. Macrophages, inflammation and risk of cervical intraepithelial neoplasia (CIN) progression- Clinicopathological correlation. Gynecol Oncol. 2007;105(1):157–165. doi:10.1016/j.ygyno.2006.11.02317229459
  • Ding H, Cai J, Mao M, et al. Tumor-associated macrophages induce lymphangiogenesis in cervical cancer via interaction with tumor cells. Apmis. 2014;122(11):1059–1069. doi:10.1111/apm.1225724698523
  • Chen XJ, Han LF, Wu XG, et al. Clinical significance of CD163+ and CD68+ tumor-associated macrophages in high-risk HPV-related cervical cancer. J Cancer. 2017;8(18):3868–3875. doi:10.7150/jca.2144429151975
  • Swangphon P, Pientong C, Sunthamala N, et al. Correlation of circulating CD64(+)/CD163(+) monocyte ratio and stroma/peri-tumoral CD163(+) monocyte density with human papillomavirus infected cervical lesion severity. Cancer Microenviron. 2017;10(1–3):77–85. doi:10.1007/s12307-017-0200-229064053
  • Jiang S, Yang Y, Fang M, Li X, Yuan X, Yuan J. Co-evolution of tumor-associated macrophages and tumor neo-vessels during cervical cancer invasion. Oncol Lett. 2016;12(4):2625–2631. doi:10.3892/ol.2016.501427698836
  • Stone SC, Rossetti RAM, Alvarez KLF, et al. Lactate secreted by cervical cancer cells modulates macrophage phenotype. J Leukoc Biol. 2019;105(5):1041–1054. doi:10.1002/JLB.3A0718-274RR30811636
  • Sanchez-Reyes K, Bravo-Cuellar A, Hernandez-Flores G, et al. Cervical cancer cell supernatants induce a phenotypic switch from U937-derived macrophage-activated M1 state into M2-like suppressor phenotype with change in Toll-like receptor profile. Biomed Res Int. 2014;2014:683068. doi:10.1155/2014/68306825309919
  • Chen XJ, Wu S, Yan RM, et al. The role of the hypoxia-Nrp-1 axis in the activation of M2-like tumor-associated macrophages in the tumor microenvironment of cervical cancer. Mol Carcinog. 2019;58(3):388–397. doi:10.1002/mc.2293630362630
  • Liang Y, Lu B, Zhao P, Lu W. Increased circulating GrMyeloid-derived suppressor cells correlated with tumor burden and survival in locally advanced cervical cancer patient. J Cancer. 2019;10(6):1341–1348. doi:10.7150/jca.2964731031843
  • Wu L, Liu H, Guo H, et al. Circulating and tumor-infiltrating myeloid-derived suppressor cells in cervical carcinoma patients. Oncol Lett. 2018;15(6):9507–9515. doi:10.3892/ol.2018.853229844835
  • Lee BR, Kwon BE, Hong EH, et al. Interleukin-10 attenuates tumour growth by inhibiting interleukin-6/signal transducer and activator of transcription 3 signalling in myeloid-derived suppressor cells. Cancer Lett. 2016;381(1):156–164. doi:10.1016/j.canlet.2016.07.01227431309
  • Heeren AM, Koster BD, Samuels S, et al. High and interrelated rates of PD-L1+CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer. Cancer Immunol Res. 2015;3(1):48–58. doi:10.1158/2326-6066.CIR-14-014925361854
  • Li X, Wang R, Fan P, et al. A comprehensive analysis of key immune checkpoint receptors on tumor-infiltrating T cells from multiple types of cancer. Front Oncol. 2019;9:1066. doi:10.3389/fonc.2019.0106631709176
  • Zhen S, Lu J, Liu YH, Chen W, Li X. Synergistic antitumor effect on cervical cancer by rational combination of PD1 blockade and CRISPR-Cas9-mediated HPV knockout. Cancer Gene Ther. 2019;27:1–11.31292516
  • Hu S, Pu D, Xia X, Guo B, Zhang C. CTLA-4 rs5742909 polymorphism and cervical cancer risk: a meta-analysis. Medicine (Baltimore). 2020;99(11):e19433. doi:10.1097/MD.000000000001943332176070
  • Karpathiou G, Chauleur C, Mobarki M, Peoc’h M. The immune checkpoints CTLA-4 and PD-L1 in carcinomas of the uterine cervix. Pathol Res Pract. 2020;216(1):152782. doi:10.1016/j.prp.2019.15278231862202
  • Yang W, Song Y, Lu YL, Sun JZ, Wang HW. Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia. Immunology. 2013;139(4):513–522. doi:10.1111/imm.1210123521696
  • Heeren AM, Rotman J, Stam AGM, et al. Efficacy of PD-1 blockade in cervical cancer is related to a CD8(+)FoxP3(+)CD25(+) T-cell subset with operational effector functions despite high immune checkpoint levels. J Immunother Cancer. 2019;7(1):43. doi:10.1186/s40425-019-0526-z30755279
  • Dorta-Estremera S, Hegde VL, Slay RB, et al. Targeting interferon signaling and CTLA-4 enhance the therapeutic efficacy of anti-PD-1 immunotherapy in preclinical model of HPV(+) oral cancer. J Immunother Cancer. 2019;7(1):252. doi:10.1186/s40425-019-0728-431533840
  • Lheureux S, Butler MO, Clarke B, et al. Association of ipilimumab with safety and antitumor activity in women with metastatic or recurrent human papillomavirus-related cervical carcinoma. JAMA Oncol. 2018;4(7):e173776. doi:10.1001/jamaoncol.2017.377629145543
  • Rotman J, Mom CH, Jordanova ES, de Gruijl TD, Kenter GG. ‘DURVIT’: a phase-I trial of single low-dose durvalumab (Medi4736) IntraTumourally injected in cervical cancer: safety, toxicity and effect on the primary tumour- and lymph node microenvironment. BMC Cancer. 2018;18(1):888. doi:10.1186/s12885-018-4764-030208866
  • Jung KH, LoRusso P, Burris H, et al. Phase I study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) administered with PD-L1 inhibitor (atezolizumab) in advanced solid tumors. Clin Cancer Res. 2019;25(11):3220–3228. doi:10.1158/1078-0432.CCR-18-274030770348
  • Mayadev J, Zamarin D, Deng W, et al. Anti-PD-L1 (atezolizumab) as an immune primer and concurrently with extended-field chemoradiotherapy for node-positive locally advanced cervical cancer. Int J Gynecol Cancer. 2019;30.
  • Chinn Z, Stoler MH, Mills AM. PD-L1 and IDO expression in cervical and vulvar invasive and intraepithelial squamous neoplasias: implications for combination immunotherapy. Histopathology. 2019;74(2):256–268. doi:10.1111/his.1372330067880
  • Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(34):4015–4022. doi:10.1200/JCO.2015.62.339726351349
  • Huang RY, Francois A, McGray AR, Miliotto A, Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2017;6(1):e1249561. doi:10.1080/2162402X.2016.124956128197366
  • 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. 2019;145(6):1651–1660. doi:10.1007/s00432-019-02915-130972492
  • Zacharakis N, Chinnasamy H, Black M, et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med. 2018;24(6):724–730. doi:10.1038/s41591-018-0040-829867227
  • Zhang R, Zhang Z, Liu Z, et al. Adoptive cell transfer therapy for hepatocellular carcinoma. Front Med. 2019;13(1):3–11. doi:10.1007/s11684-019-0684-x30659408
  • 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. doi:10.1007/s00262-016-1892-827619514
  • McCormack SE, Cruz CRY, Wright KE, et al. Human papilloma virus-specific T cells can be generated from naive T cells for use as an immunotherapeutic strategy for immunocompromised patients. Cytotherapy. 2018;20(3):385–393. doi:10.1016/j.jcyt.2017.11.01029331266
  • Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–2554. doi:10.1056/NEJMoa170856629226764
  • He Y, Li XM, Yin CH, Wu YM. Killing cervical cancer cells by specific chimeric antigen receptor-modified T cells. J Reprod Immunol. 2020;139:103115. doi:10.1016/j.jri.2020.10311532199196
  • Li N, Tian YW, Xu Y, et al. Combined treatment with autologous CIK cells, radiotherapy and chemotherapy in advanced cervical cancer. Pathol Oncol Res. 2019;25(2):691–696. doi:10.1007/s12253-018-0541-230511107
  • Veluchamy JP, Heeren AM, Spanholtz J, et al. High-efficiency lysis of cervical cancer by allogeneic NK cells derived from umbilical cord progenitors is independent of HLA status. Cancer Immunol Immunother. 2017;66(1):51–61. doi:10.1007/s00262-016-1919-127783105
  • Langers I, Renoux V, Reschner A, et al. Natural killer and dendritic cells collaborate in the immune response induced by the vaccine against uterine cervical cancer. Eur J Immunol. 2014;44(12):3585–3595. doi:10.1002/eji.20144459425229656
  • Choi YW, Kang MC, Seo YB, et al. Intravaginal administration of Fc-fused IL7 suppresses the cervicovaginal tumor by recruiting HPV DNA vaccine-induced CD8 T cells. Clin Cancer Res. 2016;22(23):5898–5908. doi:10.1158/1078-0432.CCR-16-042327407095
  • Grunwitz C, Salomon N, Vascotto F, et al. HPV16 RNA-LPX vaccine mediates complete regression of aggressively growing HPV-positive mouse tumors and establishes protective T cell memory. Oncoimmunology. 2019;8(9):e1629259. doi:10.1080/2162402X.2019.162925931428528
  • Baghban Rahimi S, Mohebbi A, Vakilzadeh G, et al. Enhancement of therapeutic DNA vaccine potency by melatonin through inhibiting VEGF expression and induction of antitumor immunity mediated by CD8+ T cells. Arch Virol. 2018;163(3):587–597. doi:10.1007/s00705-017-3647-z29149434
  • Atherton MJ, Stephenson KB, Nikota JK, et al. Preclinical development of peptide vaccination combined with oncolytic MG1-E6E7 for HPV-associated cancer. Vaccine. 2018;36(16):2181–2192. doi:10.1016/j.vaccine.2018.02.07029544689
  • Yang Y, Che Y, Zhao Y, Wang X. 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. 2019;69:279–288. doi:10.1016/j.intimp.2019.01.02430743204
  • Dorta-Estremera S, Chin RL, Sierra G, et al. Mucosal HPV E6/E7 peptide vaccination in combination with immune checkpoint modulation induces regression of HPV(+) oral cancers. Cancer Res. 2018;78(18):5327–5339. doi:10.1158/0008-5472.CAN-18-089230054333
  • Vici P, Pizzuti L, Mariani L, et al. Targeting immune response with therapeutic vaccines in premalignant lesions and cervical cancer: hope or reality from clinical studies. Expert Rev Vaccines. 2016;15(10):1327–1336. doi:10.1080/14760584.2016.117653327063030
  • Trimble CL, Morrow MP, Kraynyak KA, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet. 2015;386(10008):2078–2088. doi:10.1016/S0140-6736(15)00239-126386540
  • Barra F, Della Corte L, Noberasco G, et al. Advances in therapeutic vaccines for treating human papillomavirus-related cervical intraepithelial neoplasia. J Obstet Gynaecol Res. 2020;46(7):989–1006. doi:10.1111/jog.1427632390320
  • Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol. 2015;33(18):2092–2099. doi:10.1200/JCO.2014.60.037925918278
  • Lagunas-Cruz MDC, Valle-Mendiola A, Trejo-Huerta J, et al. IL-2 induces transient arrest in the G1 phase to protect cervical cancer cells from entering apoptosis. J Oncol. 2019;2019:7475295. doi:10.1155/2019/747529531662754
  • Morgan EL, Macdonald A, Galloway DA. Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Rac1-NFκB-IL-6 signalling axis. PLoS Pathog. 2019;15(6):e1007835. doi:10.1371/journal.ppat.100783531226168
  • Rangel-Corona R, Corona-Ortega T, Soto-Cruz I, et al. Evidence that cervical cancer cells secrete IL-2, which becomes an autocrine growth factor. Cytokine. 2010;50(3):273–277. doi:10.1016/j.cyto.2010.02.01320227890
  • Du GH, Wang JK, Richards JR, Wang JJ. Genetic polymorphisms in tumor necrosis factor alpha and interleukin-10 are associated with an increased risk of cervical cancer. Int Immunopharmacol. 2019;66:154–161. doi:10.1016/j.intimp.2018.11.01530453149
  • Borgogna JC, Shardell MD, Santori EK, et al. The vaginal metabolome and microbiota of cervical HPV-positive and HPV-negative women: a cross-sectional analysis. Bjog. 2019;127:182–192.31749298