A novel prognostic index based on autophagy-related genes—the Achilles' heel of cervical squamous cell carcinoma

Despite sustained advances in the diagnosis and treatment of cervical squamous cell carcinoma (CESC), patients with advanced or recurrent CESC are prone to a poor prognosis. Accumulating evidence suggests that autophagy-related genes (ARGs) are prominent indicators of CESC prognosis. Transcriptomic and clinical data of CESC patients were obtained from The Cancer Genome Atlas (TCGA) database to calculate an autophagy-related gene prognostic index (API) based on the hub genes using a least absolute shrinkage and selection operator (Lasso)-Cox regression model. Its efficacy in predicting the overall survival (OS) and immunotherapeutic responses of CESC patients was assessed. Three autophagy-related genes, B cell leukemia/lymphoma 2 (BCL2) and tumor protein p73 (TP73), were independent prognostic factors of CESC and were used to obtain API. Patients with high API showed better OS, along with enhanced infiltration of (cluster of differentiation 8+) CD8+ T and Treg cells, inhibition of activated natural killer (NK) cells, and activation of dendritic cell infiltration in CESC tissues. As compared to those with low API, patients with a high API showed enhanced expressions of immune checkpoints, including programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA4), and lower half maximal inhibitory concentration (IC50) values for common chemotherapy agents, including paclitaxel and cisplatin. Collectively, low expression of ARGs, namely BCL2 and TP73, may be the Achilles’ heel for CESC. API could accurately predict the prognosis and efficacy of immunotherapy and chemotherapy for CESC patients.

Cervical squamous cell carcinoma; Prognosis; Immunotherapy; Chemotherapy

[1] 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: A Cancer Journal for Clinicians. 2018; 68: 394–424.

[2] Sharma S, Deep A, Sharma AK. Current treatment for cervical cancer: an update. Anti-Cancer Agents in Medicinal Chemistry. 2020; 20: 1768–1779.

[3] Eskander RN, Tewari KS. Chemotherapy in the treatment of metastatic, persistent, and recurrent cervical cancer. Current Opinion in Obstetrics & Gynecology. 2014; 26: 314–321.

[4] Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. The New England Journal of Medicine. 1999; 340: 1144–1153.

[5] Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. The New England Journal of Medicine. 2017; 376: 1015–1026.

[6] Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. Journal of Hematology & Oncology. 2019; 12: 47.

[7] Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. Journal of Clinical Oncology. 2019; 37: 1470–1478.

[8] Naumann RW, Hollebecque A, Meyer T, Devlin M, Oaknin A, Kerger J, 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. Journal of Clinical Oncology. 2019; 37: 2825–2834.

[9] Ventriglia J, Paciolla I, Pisano C, Cecere SC, Di Napoli M, Tambaro R, et al. Immunotherapy in ovarian, endometrial and cervical cancer: State of the art and future perspectives. Cancer Treatment Reviews. 2017; 59: 109–116.

[10] Otter SJ, Chatterjee J, Stewart AJ, Michael A. The role of biomarkers for the prediction of response to checkpoint immunotherapy and the rationale for the use of checkpoint immunotherapy in cervical cancer. Clinical Oncology. 2019; 31: 834–843.

[11] Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nature Reviews Cancer. 2005; 5: 726–734.

[12] Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Molecular Cancer. 2020; 19: 12.

[13] Xia H, Green DR, Zou W. Autophagy in tumour immunity and therapy. Nature Reviews Cancer. 2021; 21: 281–297.

[14] Gerada C, Ryan KM. Autophagy, the innate immune response and cancer. Molecular Oncology. 2020; 14: 1913–1929.

[15] White E, Mehnert JM, Chan CS. Autophagy, Metabolism, and Cancer. Clinical Cancer Research. 2015; 21: 5037–5046.

[16] Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nature Methods. 2015; 12: 453–457.

[17] Frenel JS, Le Tourneau C, O’Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. Journal of Clinical Oncology. 2017; 35: 4035–4041.

[18] Mayadev JS, Enserro D, Lin YG, Da Silva DM, Lankes HA, Aghajanian C, et al. Sequential ipilimumab after chemoradiotherapy in curative-intent treatment of patients with node-positive cervical cancer. JAMA Oncology. 2020; 6: 92–99.

[19] Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. The New England Journal of Medicine. 2021; 385: 1856–1867.

[20] Duska LR, Scalici JM, Temkin SM, Schwarz JK, Crane EK, Moxley KM, et al. Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer. Cancer. 2020; 126: 4948–4956.

[21] Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011; 147: 728–741.

[22] Harris J. Autophagy and cytokines. Cytokine. 2011; 56: 140–144.

[23] Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020; 581: 100–105.

[24] Robainas M, Otano R, Bueno S, Ait-Oudhia S. Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy. OncoTargets and Therapy. 2017; 10: 1803–1807.

[25] Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, inflammation, and immunity: a troika governing cancer and its treatment. Cell. 2016; 166: 288–298.

[26] Bortnik S, Gorski SM. Clinical applications of autophagy proteins in cancer: from potential targets to biomarkers. International Journal of Molecular Sciences. 2017; 18: 1496.

[27] Ma M, Xie W, Li X. Identification of autophagy-related genes in the progression from non-alcoholic fatty liver to non-alcoholic steatohepatitis. International Journal of General Medicine. 2021; 14: 3163–3176.

[28] Hardwick JM, Soane L. Multiple functions of BCL-2 family proteins. Cold Spring Harbor Perspectives in Biology. 2013; 5: a008722.

[29] Martínez-Arribas F, Alvarez T, Del Val G, Martín-Garabato E, Núñez-Villar MJ, Lucas R, et al. Bcl-2 expression in breast cancer: a comparative study at the mRNA and protein level. Anticancer Research. 2007; 27: 219–222.

[30] Yao Q, Chen J, Lv Y, Wang T, Zhang J, Fan J, et al. The significance of expression of autophagy-related gene Beclin, Bcl-2, and Bax in breast cancer tissues. Tumour Biology. 2011; 32: 1163–1171.

[31] Logotheti S, Richter C, Murr N, Spitschak A, Marquardt S, Pützer BM. Mechanisms of functional pleiotropy of p73 in cancer and beyond. Frontiers in Cell and Developmental Biology. 2021; 9: 737735.

[32] Ye H, Guo X. TP73 is a credible biomarker for predicting clinical progression and prognosis in cervical cancer patients. Bioscience Reports. 2019; 39: BSR20190095.

[33] Zhang L, Jiang Y, Lu X, Zhao H, Chen C, Wang Y, et al. Genomic characterization of cervical cancer based on human papillomavirus status. Gynecologic Oncology. 2019; 152: 629–637.

[34] Burki TK. Novel mutations in cervical cancer. The Lancet. Oncology. 2017; 18: e137.

[35] Shen H, Guo M, Wang L, Cui X. MUC16 facilitates cervical cancer progression via JAK2/STAT3 phosphorylation-mediated cyclooxygenase-2 expression. Genes & Genomics. 2020; 42: 127–133.

[36] Togami S, Nomoto M, Higashi M, Goto M, Yonezawa S, Tsuji T, et al. Expression of mucin antigens (MUC1 and MUC16) as a prognostic factor for mucinous adenocarcinoma of the uterine cervix. The Journal of Obstetrics and Gynaecology Research. 2010; 36: 588–597.

[37] Li X, Pasche B, Zhang W, Chen K. Association of MUC16 mutation with tumor mutation load and outcomes in patients with gastric cancer. JAMA Oncology. 2018; 4: 1691–1698.

[38] Farhood B, Najafi M, Mortezaee K. CD8(+) cytotoxic T lymphocytes in cancer immunotherapy: a review. Journal of Cellular Physiology. 2019; 234: 8509–8521.

[39] Knochelmann HM, Dwyer CJ, Bailey SR, Amaya SM, Elston DM, Mazza-McCrann JM, et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cellular & Molecular Immunology. 2018; 15: 458–469.

[40] Bigley AB, Simpson RJ. NK cells and exercise: implications for cancer immunotherapy and survivorship. Discovery Medicine. 2015; 19: 433–445.

[41] Shimasaki N, Jain A, Campana D. NK cells for cancer immunotherapy. Nature Reviews Drug Discovery. 2020; 19: 200–218.

[42] Sun C, Mezzadra R, Schumacher TN. Regulation and function of the PD-L1 checkpoint. Immunity. 2018; 48: 434–452.

[43] Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. The Lancet. Oncology. 2016; 17: e542–e551.

[44] Yamazaki T, Bravo-San Pedro JM, Galluzzi L, Kroemer G, Pietrocola F. Autophagy in the cancer-immunity dialogue. Advanced Drug Delivery Reviews. 2021; 169: 40–50.

[45] Yousefi S, Simon HU. Autophagy in cancer and chemotherapy. Results and Problems in cell Differentiation. 2009; 49: 183–190.