Cancer Research on Prevention and Treatment    2022, Vol. 49 Issue (09) : 886-892     DOI: 10.3971/j.issn.1000-8578.2022.22.0162
Countermeasures and Mechanisms of Drug Resistance in Immunotherapy for Cervical Cancer
YANG Junyuan, CAI Hongbing
Department of Gynecology and Oncology, Zhongnan Hospital of Wuhan University, Hubei Medical Oncology Research Center, Hubei Key Laboratory of Tumor Biological Behavior, Wuhan 430071, China    
Download: PDF(14902 KB)   ( 41 )   HTML ()
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract Cervical cancer has become a serious threat to women's health worldwide, advanced cervical cancer has limited treatment options. 5-year survival rate is less than 20%, which is a huge challenge for the gynecologic oncology community. Immunotherapy is one of the important treatment for patients with advanced cervical cancer. including immune checkpoint inhibitors, therapeutic vaccines, and periprocedural T-cell immunotherapy, etc. However, immunotherapy resistance makes some patients non-responsive and ineffective. Therefore, there is an urgent need to study and explore the mechanism of immune resistance to improve drug resistance. The present review summarizes the relevant studies on the mechanism of immune resistance in cervical cancer in recent years, mainly divided into factors such as intrinsic tumor and altered external immune environment, and introduces the countermeasures and progresses proposed for immune resistance.
Keywords Cervical cancer      Immunotherapy      Drug resistance      Immune escape      Immune checkpoint inhibitors     
ZTFLH:  R737.33  
Issue Date: 15 September 2022
 Cite this article:   
YANG Junyuan,CAI Hongbing. Countermeasures and Mechanisms of Drug Resistance in Immunotherapy for Cervical Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(09): 886-892.
E-mail this article
E-mail Alert
Articles by authors
YANG Junyuan
CAI Hongbing
[1] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020:<br /> GLOBOCAN Estimates of Incidence and Mortality Worldwide<br /> for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021,<br /> 71(3): 209-249.<br /> [2] Malla R, Kamal MA. E6 and E7 Oncoproteins: Potential Targets<br /> of Cervical Cancer[J]. Curr Med Chem, 2021, 28(39): 8163-8181.<br /> [3] 中国抗癌协会妇科肿瘤专业委员会. 子宫颈癌诊断与治疗<br /> 指南(2021年版)[J]. 中国癌症杂志, 2021, 31(6): 474-489.<br /> [Gynecological oncology Committee of China Anti-Cancer<br /> Association. Diagnosis and treatment guidelines for cervical<br /> cancer (2021 Edition)[J]. Zhongguo Ai Zheng Za Zhi, 2021,<br /> 31(6): 474-489.]<br /> [4] Mauricio D, Zeybek B, Tymon-Rosario J, et al. Immunotherapy in<br /> Cervical Cancer[J]. Curr Oncol Rep, 2021, 23(6): 61.<br /> [5] Frenel JS, Le Tourneau C, O'Neil B, et al. Safety and Efficacy<br /> of Pembrolizumab in Advanced, Programmed Death Ligand<br /> 1-Positive Cervical Cancer: Results From the PhaseⅠb<br /> KEYNOTE-028 Trial[J]. J Clin Oncol, 2017, 35(36): 4035-4041.<br /> [6] Duan Q, Zhang H, Zheng J, et al. Turning Cold into Hot: Firing<br /> up the Tumor Microenvironment[J]. Trends Cancer, 2020, 6(7):<br /> 605-618.<br /> [7] Heeren AM, Koster BD, Samuels S, et al. High and interrelated<br /> rates of PD-L1+CD14+ antigen-presenting cells and regulatory T<br /> cells mark the microenvironment of metastatic lymph nodes from<br /> patients with cervical cancer[J]. Cancer Immunol Res, 2015, 3(1):<br /> 48-58.<br /> [8] Tang Y, Zhang AXJ, Chen G, et al. Prognostic and therapeutic TILs<br /> of cervical cancer-Current advances and future perspectives[J].<br /> Mol Ther Oncolytics, 2021, 22: 410-430.<br /> [9] Welters MJ, van der Sluis TC, van Meir H, et al. Vaccination<br /> during myeloid cell depletion by cancer chemotherapy fosters<br /> robust T cell responses[J]. Sci Transl Med, 2016, 8(334): 334ra52.<br /> [10] Alvarez KLF, Beldi M, Sarmanho F, et al. Local and systemic<br /> immunomodulatory mechanisms triggered by Human<br /> Papillomavirus transformed cells: a potential role for G-CSF and<br /> neutrophils[J]. Sci Rep, 2017, 7(1): 9002.<br /> [11] Galliverti G, Wullschleger S, Tichet M, et al. Myeloid Cells<br /> Orchestrate Systemic Immunosuppression, Impairing the Efficacy<br /> of Immunotherapy against HPV+ Cancers[J]. Cancer Immunol<br /> Res, 2020, 8(1): 131-145.<br /> [12] Rotman J, Mom CH, Jordanova ES, et al. 'DURVIT': a phase-I<br /> trial of single low-dose durvalumab (Medi4736) IntraTumourally<br /> injected in cervical cancer: safety, toxicity and effect on the<br /> primary tumour- and lymph node microenvironment[J]. BMC<br /> Cancer, 2018, 18(1): 888.<br /> [13] Cruz E, Kayser V. Monoclonal antibody therapy of solid tumors:<br /> clinical limitations and novel strategies to enhance treatment<br /> efficacy[J]. Biologics, 2019, 13: 33-51.<br /> [14] Medema JP, de Jong J, Peltenburg LT, et al. Blockade of the<br /> granzyme B/perforin pathway through overexpr‍ession of the<br /> serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for<br /> immune escape by tumors[J]. Proc Natl Acad Sci U S A, 2001,<br /> 98(20): 11515-11520.<br /> [15] Schoenfeld AJ, Hellmann MD. Acquired Resistance to Immune<br /> Checkpoint Inhibitors[J]. Cancer Cell, 2020, 37(4): 443-455.<br /> [16] Li X, Wang R, Fan P, et al. A Comprehensive Analysis of Key<br /> Immune Checkpoint Receptors on Tumor-Infiltrating T Cells<br /> From Multiple Types of Cancer[J]. Front Oncol, 2019, 9: 1066.<br /> [17] Wang Y, Zhao S, Zhang X, et al. Higher T cell immunoglobulin<br /> mucin-3 (Tim-3) expr‍ession in cervical cancer is associated<br /> with a satisfactory prognosis[J]. Transl Cancer Res, 2020, 9(4):<br /> 2801-2813.<br /> [18] Chen F, Sherwood T, Costa AD, et al. Immunohistochemistry<br /> analyses of LAG-3 expr‍ession across different tumor types and<br /> co-expr‍ession with PD-1[J]. J Clin Oncol, 2020, 38(15_suppl):<br /> e15086.<br /> [19] Andrews LP, Marciscano AE, Drake CG, et al. LAG3 (CD223) as<br /> a cancer immunotherapy target[J]. Immunol Rev, 2017, 276(1):<br /> 80-96.<br /> [20] Simon S, Voillet V, Vignard V, et al. PD-1 and TIGIT coexpr‍ession<br /> identifies a circulating CD8 T cell subset predictive of response to<br /> anti-PD-1 therapy[J]. Immunother Cancer, 2020, 8(2): e001631.<br /> [21] Qin S, Xu L, Yi M, et al. Novel immune checkpoint targets:<br /> moving beyond PD-1 and CTLA-4[J]. Mol Cancer, 2019, 18(1):<br /> 155.<br /> [22] Chinn Z, Stoler MH, Mills AM. PD-L1 and IDO expr‍ession<br /> in cervical and vulvar invasive and intraepithelial squamous<br /> neoplasias: implications for combination immunotherapy[J].<br /> Histopathology, 2019, 74(2): 256-268.<br /> [23] Mills A, Zadeh S, Sloan E, et al. Indoleamine 2,3-dioxygenase in<br /> endometrial cancer: a targetable mechanism of immune resistance<br /> in mismatch repair-deficient and intact endometrial carcinomas[J].<br /> Mod Pathol, 2018, 31(8): 1282-1290.<br /> [24] Taube JM, Klein A, Brahmer JR, et al. Association of PD-1,<br /> PD-1 ligands, and other features of the tumour immune<br /> microenvironment with response to anti-PD-1 therapy[J]. Clin<br /> Cancer Res, 2014, 20(19): 5064-5074.<br /> [25]Hamid O, Bauer TM, Spira AI, et al. Epacadostat plus<br /> pembrolizumab in patients with SCCHN: preliminary phase I/II<br /> results from ECHO-202/KEYNOTE-037[J]. Clin Oncol, 2017,<br /> 35(15): 6010.<br /> [26] Scholl S, Popovic M, de la Rochefordiere A, et al. Clinical and<br /> genetic landscape of treatment naive cervical cancer: Alterations<br /> in PIK3CA and in epigenetic modulators associated with suboptimal<br /> outcome[J]. EBioMedicine, 2019, 43: 253-260.<br /> [27] O’Donnell JS, Massi D, Teng MWL, et al. PI3K-AKT-mTOR<br /> inhibition in cancer immunotherapy, redux[J]. Semin Cancer Biol,<br /> 2018, 48: 91-103.<br /> [28] De H, Rausch M, Winkler D, et al. Overcoming resistance to<br /> checkpoint blockade therapy by targeting PI3Kgamma in myeloid<br /> cells[J]. Nature, 2016, 539: 443-447.<br /> [29] Peng W, Chen JQ, Liu C, et al. Loss of PTEN Promotes Resistance<br /> to T Cell-Mediated Immunotherapy[J]. Cancer Discov, 2016, 6(2):<br /> 202-216.<br /> [30] George S, Miao D, Demetri GD, et al. Loss of PTEN Is Associated<br /> with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in<br /> Metastatic Uterine Leiomyosarcoma[J]. Immunity, 2017, 46(2):<br /> 197-204.<br /> [31] Tamura R, Tanaka T, Akasaki Y, et al. The role of vascular<br /> endothelial growth factor in the hypoxic and immunosuppressive<br /> tumor microenvironment: perspectives for therapeutic<br /> implications[J]. Med Oncol, 2019, 37(1): 2.<br /> [32] Lan C, Shen J, Wang Y, et al. Camrelizumab Plus Apatinib in<br /> Patients With Advanced Cervical Cancer (CLAP): A Multicenter,<br /> Open-Label, Single-Arm, Phase Ⅱ Trial[J]. J Clin Oncol, 2020, 38(34): 4095-4106.<br /> [33] Grau JF, Farinas-Madrid L, Oaknin A. A randomized phase Ⅲ trial<br /> of platinum chemotherapy plus paclitaxel with bevacizumab and<br /> atezolizumab versus platinum chemotherapy plus paclitaxel and<br /> bevacizumab in metastatic (stage IVB), persistent, or recurrent<br /> carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/<br /> GEICO 68-C/JGOG1084/GOG-3030)[J]. Int J Gynecol Cancer,<br /> 2020, 30(1): 139-143.<br /> [34] Noh KH, Kim BW, Song KH, et al. Nanog signaling in cancer<br /> promotes stem-like phenotype and immune evasion[J]. J Clin<br /> Invest, 2012, 122(11): 4077-4093.<br /> [35] Kim S, Cho H, Hong SO, et al. LC3B upregulation by NANOG<br /> promotes immune resistance and stem-like property through<br /> hyperactivation of EGFR signaling in immune-refractory tumor<br /> cells[J]. Autophagy, 2021, 17(8): 1978-1997.<br /> [36] Song KH, Choi CH, Lee HJ, et al. HDAC1 Upregulation by<br /> NANOG Promotes Multidrug Resistance and a Stem-like<br /> Phenotype in Immune Edited Tumor Cells[J]. Cancer Res, 2017,<br /> 77(18): 5039-5053.<br /> [37] Friedrich M, Jasinski-Bergner S, Lazaridou MF, et al. Tumorinduced<br /> escape mechanisms and their association with resistance<br /> to checkpoint inhibitor therapy [J]. Cancer Immunol Immunother,<br /> 2019, 68(10):1689-1700.<br /> [38] Dibbern ME, Bullock TN, Jenkins TM, et al. Loss of MHC Class<br /> I Expression in HPV-associated Cervical and Vulvar Neoplasia:<br /> A Potential Mechanism of Resistance to Checkpoint Inhibition[J].<br /> Am J Surg Pathol, 2020, 44(9): 1184-1191.<br /> [39] Gettinger S, Choi J, Hastings K, et al. Impaired HLA Class I<br /> Antigen Processing and Presentation as a Mechanism of Acquired<br /> Resistance to Immune Checkpoint Inhibitors in Lung Cancer[J].<br /> Cancer Discov, 2017, 7(12): 1420-1435.<br /> [40] Rassy E, Boussios S, Pavlidis N. Genomic correlates of response<br /> and resistance to immune checkpoint inhibitors in carcinomas of<br /> unknown primary[J]. Eur J Clin Invest, 2021, 51(9): e13583.<br /> [41] Kang TH, Noh KH, Kim JH, et al. Ectopic expr‍ession of X-linked<br /> lymphocyte-regulated protein pM1 renders tumor cells resistant to<br /> antitumor immunity[J]. Cancer Res, 2010, 70(8): 3062-3070.<br /> [42]Gutiérrez-Hoya A, Soto-Cruz I. Role of the JAK/STAT<br /> Pathway in Cervical Cancer: Its Relationship with HPV E6/E7<br /> Oncoproteins[J]. Cells, 2020, 9(10): 2297.<br /> [43] Morgan EL, Macdonald A. Autocrine STAT3 activation in HPV<br /> positive cervical cancer through a virus-driven Rac1-NFκB-IL-6<br /> signalling axis[J]. PLoS Pathog, 2019, 15(6): e1007835.<br /> [44] Joseph A, Pan J, Michels J, et al. Pyridoxal kinase and poly(ADPribose)<br /> affect the immune microenvironment of locally advanced<br /> cancers[J]. Oncoimmunology, 2021, 10(1): 1950954.<br /> [45] Gotwals P, Cameron S, Cipolletta D, et al. Prospects for combining<br /> targeted and conventional cancer therapy with immunotherapy[J].<br /> Nat Rev Cancer, 2017, 17(5): 286-301.<br /> [46] Sharabi AB, Lim M, DeWeese TL, et al. Radiation and checkpoint<br /> blockade immunotherapy: radiosensitisation and potential<br /> mechanisms of synergy[J]. Lancet Oncol, 2015, 16(13):<br /> e498-e509.<br /> [47] Young KH, Baird JR, Savage T, et al. Optimizing Timing of<br /> Immunotherapy Improves Control of Tumors by Hypofractionated<br /> Radiation Therapy[J]. PLoS One, 2016,11(6): e0157164.<br /> [48] Mayadev J, Zamarin D, Deng W, et al. Anti-PD-L1 (atezolizumab)<br /> as an immune primer and concurrently with extended-field<br /> chemoradiotherapy for node-positive locally advanced cervical<br /> cancer[J]. Int J Gynecol Cancer, 2020, 30(5): 701-704.<br /> [49] Meng Y, Liang H, Hu J, et al. PD-L1 Expression Correlates With<br /> Tumor Infiltrating Lymphocytes And Response To Neoadjuvant<br /> Chemotherapy In Cervical Cancer[J]. J Cancer, 2018, 9(16):<br /> 2938-2945.<br /> [50] Heeren AM, van Luijk IF, Lakeman J, et al. Neoadjuvant cisplatin<br /> and paclitaxel modulate tumor-infiltrating T cells in patients with<br /> cervical cancer[J]. Cancer Immunol Immunother, 2019, 68(11):<br /> 1759-1767.<br /> [51] Ramos da Silva J, Ramos Moreno AC, Silva Sales N, et al. A<br /> therapeutic DNA vaccine and gemcitabine act synergistically<br /> to eradicate HPV-associated tumors in a preclinical model[J].<br /> Oncoimmunology, 2021, 10(1): 1949896.<br /> [52] Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to<br /> immune checkpoint inhibitors[J]. Br J Cancer, 2018, 118(1): 9-16.<br /> [53]Rice AE, Latchman YE, Balint JP, et al. An HPV-E6/E7<br /> immunotherapy plus PD-1 checkpoint inhibition results in tumor<br /> regression and reduction in PD-L1 expr‍ession[J]. Cancer Gene<br /> Ther, 2015, 22(9): 454-462.<br /> [54] Massarelli E, William W, Johnson F, et al. Combining immune<br /> checkpoint blockade and tumor-specific vaccine for patients with<br /> incurable human papillomavirus 16-related cancer: a phase 2<br /> clinical trial[J]. JAMA Oncol, 2019, 5(1): 67-73.<br /> [55] Ginaldi L, Loreto MF, Corsi MP, et al. Immunosenescence and<br /> infectious diseases[J]. Microbes Infect, 2001, 3(10): 851-857.<br /> [56] Peng S, Qiu J, Yang A, et al. Optimization of heterologous DNAprime,<br /> protein boost regimens and site of vaccination to enhance<br /> therapeutic immunity against human papillomavirus-associated<br /> disease[J]. Cell Biosci, 2016, 6: 16.<br /> [57] Aspeslagh S, Postel-Vinay S, Rusakiewicz S, et al. Rationale for<br /> anti-OX40 cancer immunotherapy[J]. Eur J Cancer, 2016, 52:<br /> 50-66.<br /> [58] Glisson BS, Leidner RS, Ferris RL, et al. Safety and clinical<br /> activity of MEDI0562, a humanized OX40 agonist monoclonal<br /> antibody, in adult patients with advanced solid tumors[J]. Clin<br /> Cancer Res, 2020, 26(20): 5358-5367.<br /> [59] Padovani CT, Bonin CM, Tozetti IA, et al. Glucocorticoid-induced<br /> tumor necrosis factor receptor expr‍ession in patients with cervical<br /> human papillomavirus infection[J]. Rev Soc Bras Med Trop, 2013,<br /> 46(3): 288-292.<br /> [60] Knee DA, Hewes B, Brogdon JL. Rationale for anti-GITR cancer<br /> immunotherapy[J]. Eur J Cancer, 2016, 67: 1-10.<br /> [61] Moesta AK, Li XY, Smyth MJ. Targeting CD39 in cancer[J]. Nat<br /> Rev Immunol, 2020, 20(12): 739-755.<br /> [62] Zhang X, Wang Y, Gari A, et al. Pan-Cancer Analysis of PARP1<br /> Alterations as Biomarkers in the Prediction of Immunotherapeutic<br /> Effects and the Association of Its Expression Levels and<br /> Immunotherapy Signatures[J]. Front Immunol, 2021, 12:721030.<br /> [63] Shankar S, Prasad D, Sanawar R, et al. TALEN based HPV-E7<br /> editing triggers necrotic cell death in cervical cancer cells[J]. Sci<br /> Rep, 2017, 7(1): 5500.<br />
Related articles from Frontiers Journals
[1] CHEN Yu, SONG Ziye, GAO Yang, CAI Hongbing. Effect of ECT2 Gene on Proliferation of Cervical Cancer Cells and Its Mechanism[J]. Cancer Research on Prevention and Treatment, 2022, 49(10): 1015-1020.
[2] CHEN Shuangqing, WU Wenbo, HAN Chaohui, CAO Shumin, ZHANG Xiaopeng, DUAN Guochen. Recent Advances in Immune Checkpoint Inhibitor-associated Pneumonitis[J]. Cancer Research on Prevention and Treatment, 2022, 49(10): 1065-1070.
[3] GUO Xin, DU Hua, SHI Yingxu, . Exosomal Delivery of Non-coding RNA Regulates Breast Bancer Drug Resistance[J]. Cancer Research on Prevention and Treatment, 2022, 49(10): 1071-1076.
[4] MAO Wanli, RAN Li, LI Jiehui, LI Fenghu, CHANG Jianying, MU Junyu, MEI Fan, HU Lili, DU Yanjun, TIAN Xue, QIN Yao, YIN Shuishui. Predictive Value of CD44v6 and EGFR Expression in Neoadjuvant Chemotherapy Sensitivity of Stage Ⅱ-Ⅲ Cervical Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(09): 937-943.
[5] YIN Zhucheng, LIANG Xinjun. Research Progress on Combined Immunotherapy for Microsatellite Stable Colorectal Cancer#br#[J]. Cancer Research on Prevention and Treatment, 2022, 49(09): 977-981.
[6] CAO Guangwen. Theoretical Update of Cancer Evo-Dev and Its Role in Targeted Immunotherapy for Hepatocellular Carcinoma[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 747-755.
[7] KANG Yikun, YUAN Peng. Advances in Treatment of Triple Negative Breast Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 812-819.
[8] YIN Zhucheng, LIANG Xinjun. Research Progress on Hyperthermia and Anti-Tumor Immunity[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 827-831.
[9] XIA Siyu, ZHAO Zitong, LI Li. Correlation Between STK11 Gene Mutation and Immunotherapy of Non-small Cell Lung Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 850-854.
[10] CHEN Weichang, SHI Tongguo, ZHU Jinghan, SUN Linqing, LI Juntao. Progress on Immunotherapy of Gastrointestinal Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 639-643.
[11] JIN Tongtong, ZHOU Chuan, WANG Chao, DA Zijian, ZHOU Fenghai, . Research Hotspots and Frontiers of Immunotherapy for Prostate Cancer: A Visual Analysis[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 667-674.
[12] XIN Tong, SUN Yue, HU Jing. Research Progress on Relation Between BTBP1 and Tumor Progression and Treatment[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 715-720.
[13] WU Wei, JING Doudou, CAO Li, PU Feifei, SHAO Zengwu. Current Status and Prospects of Immunotherapy for Osteosarcoma[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 721-726.
[14] CHEN Bojin, HU Xingyi, ZHAO Jingwen, ZHENG Aihong. Current Status of Immunotherapy in Neoadjuvant Therapy for Gastric Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 727-732.
[15] ZHANG Jianning, LIU Congwei. Progress of Novel Treatment Options for Glioma[J]. Cancer Research on Prevention and Treatment, 2022, 49(06): 505-513.
Full text