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Association between human papilloma virus 16 E6 and E7-specific T cell immune response and clinical prognosis of patients with cervical squamous cell carcinoma
Cai Hongchao1, Yuan Yuanliang2, Mayinuer Alifu3, Wang Ruozheng1
1The Third Affiliated Hospital of Xinjiang Medical University, Key Laboratory of Cancer Immunotherapy and Radiotherapy, Chinese Academy of Medical Sciences, Wulumuqi 830011, China; 2Xinjiang Key Laboratory of Oncology, Affiliated Cancer Hospital of Xinjiang Medical University, Wulumuqi 830011, China; 3Department of Radiation Oncology Ⅱ, People's Hospital of Xinjiang Uygur Autonomous Region, Wulumuqi 830001 China
AbstractObjective To investigate the relationship between human papilloma virus (HPV)16 E6/7-specific T cell immune response in the periphral blood and clinical features and prognosis of patients with cervical squamous cell carcinoma (CSCC). Methods Seventy-two patients pathologically diagnosed with CSCC admitted to Affiliated Tumor Hospital of Xinjiang Medical University from June 2013 to October 2015, and 75 healthy controls were enrolled in this study. The special responses of peripheral blood T cells to E6 and E7 overlapping peptides before treatment were detected by enzyme-linked immunosorbent assay (ELISA). The differences of frequency and intensity expression of specific immune responses between two groups were analyzed by chi-square χ2 test and nonparametric test. The correlation between antigen-specific immune response and T cell subsets was analyzed by Spearman test. Log-rank test and Cox's regression model were employed for univariate and multivariate prognostic analyses. Results The frequencies of HPV16 E6-ad E7-specific T cell responses in CSCC patients were significantly higher than those in healthy controls (51.39% vs. 29.33%,P=0.006 and 45.83% vs.25.33%,P=0.009), and the mean intensities were also considerably higher than those in healthy controls (20.00 SFC/106vs.10.76 SFC/106,P<0.001 and 16.17 SFC/106vs.10.72 SFC/106,P=0.017). The intensity of HPV16 E6-specific T cell immune response was positively correlated with the CD+4/CD+8 ratio in the peripheral blood of CSCC patients (r=0.279,P=0.018). And a strong correlation was noted between E7-specific T cell immune response intensity and increasing proportion of NK+ cells (r=0.274,P=0.020). Univariate and multivariate analyses showed that therapeutic mode (radiotherapy vs. concurrent chemoradiotherapy, HR=2.918, 95%CI 1.454-5.854, P=0.003) and E6-specific T cell response (response group vs. no response group, HR=0.491, 95%CI 0.243-0.99,P=0.047) were the independent prognostic factors influencing the clinical prognosis. The 5-year overall survival in patients with HPV16 E6-specific T cell responses was significantly higher than that in the no response group (64% vs.41%,P=0.041). Conclusions The intensity of HPV16 E6-specific T cell immune response is positively correlated with the CD+4/CD+8 ratio. No HPV16 E6-specific T cell response and radiotherapy alone are more likely to cause poor prognosis of CSCC patients.
Fund:National Natural Science Foundation of China (U1603282);Key Laboratory of Tumor Immunology and Radiotherapy, Chinese Academy of Medical Sciences Project (2019PT310021)
Corresponding Authors:
Wang Ruozheng, Email:wrz8526@vip.163.com
Cite this article:
Cai Hongchao,Yuan Yuanliang,Mayinuer Alifu et al. Association between human papilloma virus 16 E6 and E7-specific T cell immune response and clinical prognosis of patients with cervical squamous cell carcinoma[J]. Chinese Journal of Radiation Oncology, 2021, 30(4): 357-362.
Cai Hongchao,Yuan Yuanliang,Mayinuer Alifu et al. Association between human papilloma virus 16 E6 and E7-specific T cell immune response and clinical prognosis of patients with cervical squamous cell carcinoma[J]. Chinese Journal of Radiation Oncology, 2021, 30(4): 357-362.
[1] 屠晔强,唐秋,闫鼎鼎,等. 同步放化疗对伴有盆腹腔淋巴结转移的宫颈癌患者疗效分析[J]. 中华放射肿瘤学杂志, 2020, 29(6):446-450. DOI:10.3760/cma.j.cn113030-20191030-00447. Tu YQ, Tang Q, Yan DD, et al. Clinical efficacy of concurrent chemoradiotherapy in cervical cancer patients with pelvic and/or para-aortic lymph node metastasis treated with radical surgery[J]. Chin J Radiat Oncol, 2020, 29(6):446-450. DOI:10.3760/cma.j.cn113030-20191030-00447. [2] Shrivastava S, Mahantshetty U, Engineer R, et al. Cisplatin chemoradiotherapy vs. Radiotherapy in FIGO stage ⅢB squamous cell carcinoma of the uterine cervix:a randomized clinical trial[J]. JAMA Oncol, 2018, 4(4):506-513. DOI:10.1001/jamaoncol.2017.5179. [3] Wu X, Gu Z, Chen Y, et al. Application of PD-1 blockade in cancer immunotherapy[J]. Comput Struct Biotechnol J, 2019, 17:661-674. DOI:10.1016/j.csbj.2019.03.006. [4] Naumann RW, Hollebecque A, Meyer T, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma:results from the phase Ⅰ/Ⅱ checkmate 358 trial[J]. J Clin Oncol, 2019, 37(31):2825-2834. DOI:10.1200/JCO.19.00739. [5] Sasagawa T, Takagi H, Makinoda S. Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer[J]. J Infect Chemother, 2012, 18(6):807-815. DOI:10.1007/s10156-012-0485-5. [6] Tommasino M. The biology of beta human papillomaviruses[J]. Virus Res, 2017, 231:128-138. DOI:10.1016/j.virusres.2016.11.013. [7] Xia Y, Li W, Li Y, et al. The clinical value of the changes of peripheral lymphocyte subsets absolute counts in patients with non-small cell lung cancer[J]. Transl Oncol, 2020, 13(12):100849. DOI:10.1016/j.tranon.2020.100849. [8] Zhang H, Han X, Zhao B, et al. Multilayered HIV-1 gag-specific T-cell responses contribute to slow progression in HLA-A*30-B*13-C*06-positive patients[J]. AIDS, 2015, 29(9):993-1002. DOI:10.1097/QAD.0000000000 000652. [9] Yuan K, Wu X, Zhang Q, et al. Enzyme-linked immunospot assay response to recombinant CFP-10/ESAT-6 fusion protein among patients with spinal tuberculosis:implications for diagnosis and monitoring of surgical therapy[J]. Int J Infect Dis, 2013, 17(9):e733-738. DOI:10.1016/j.ijid.2013.02.027. [10] Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, et al. Integrated genomic and molecular characterization of cervical cancer[J]. Nature, 2017, 543(7645):378-384. DOI:10.1038/nature21386. [11] Vieira VC, Leonard B, White EA, et al. Human papillomavirus E6 triggers upregulation of the antiviral and cancer genomic DNA deaminase APOBEC3B[J]. mBiol, 2014, 5(6):e02234-14. DOI:10.1128/mBio.02234-14. [12] Massarelli E, William W, Johnson F, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer:a phase 2 clinical trial[J]. JAMA Oncol, 2019, 5(1):67-73. DOI:10.1001/jamaoncol.2018.4051. [13] Farhat S, Nakagawa M, Moscicki AB. Cell-mediated immune responses to human papillomavirus 16 E6 and E7 antigens as measured by interferon gamma enzyme-linked immunospot in women with cleared or persistent human papillomavirus infection[J]. Int J Gynecol Cancer, 2009, 19(4):508-512. DOI:10.1111/IGC.0b013e3181a388c4. [14] Wang YY, Zhou N, Liu HS, et al. Circulating activated lymphocyte subsets as potential blood biomarkers of cancer progression[J]. Cancer Med, 2020, 9(14):5086-5094. DOI:10.1002/cam4.3150. [15] 王李雪,王豪杰,欧阳伟炜,等. 外周血CD4+T细胞水平及CD4+/CD8+比值对Ⅳ期非小细胞肺癌生存影响[J]. 中华放射肿瘤学杂志, 2020, 29(9):751-756. DOI:10.3760/cma.j.cn113030-20200 329-00143. Wang LX, Wang HJ, Ouyang WW,et al. Effect of CD+4 T cells and CD+4/CD+8 in peripheral blood on survival of patients with stage Ⅳ non-small cell lung cancer[J]. Chin J Radiat Oncol, 2020, 29(9):751-756. DOI:10.3760/cma.j.cn113030-20200329-00143. [16] Bagarazzi ml, Yan J, Morrow MP, et al. Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses[J]. Sci Transl Med, 2012, 4(155):155ra138. DOI:10.1126/scitranslmed.3004414. [17] Hammer Q, Romagnani C. OMIP-039:detection and analysis of human adaptive NKG2C (+) natural killer cells[J]. Cytometry A, 2017, 91(10):997-1000. DOI:10.1002/cyto. a.23168. [18] Nakagawa M, Gupta SK, Coleman HN, et al. A favorable clinical trend is associated with CD8 T-cell immune responses to the human papillomavirus type 16 e6 antigens in women being studied for abnormal pap smear results[J]. J Low Genit Tract Dis, 2010, 14(2):124-129. DOI:10.1097/LGT.0b013e3 181c6f01e. [19] Tian T, Gong X, Gao X, et al. Comparison of survival outcomes of locally advanced cervical cancer by histopathological types in the surveillance, epidemiology, and end results (SEER) database:a propensity score matching study[J]. Infect Agent Cancer, 2020, 15(1):33. DOI:10.1186/s1302 7-020-00299-3. [20] Maciag PC, Radulovic S, Rothman J. The first clinical use of a live-attenuated Listeria monocytogenes vaccine:a Phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix[J]. Vaccine, 2009, 27(30):3975-3983. DOI:10.1016/j.vaccine.2009.04.041. [21] Hancock G, Hellner K, Dorrell L. Therapeutic HPV vaccines[J]. Best Pract Res Clin Obstet Gynaecol, 2018, 47:59-72. DOI:10.1016/j.bpobgyn.2017.09.008.