Stratification of risk based on immune signatures and prediction of the efficacy of immune checkpoint inhibitors in prostate cancer

Prostate adenocarcinoma (PRAD) is a major threat to male health worldwide with a high mortality rate. New therapeutic strategies for the treatment of this malignant disease are of tremendous significance. Much attention has been paid to the involvement of immune cells in the prevention and treatment of cancer as well as how their regulatory systems contribute to effective cancer treatment. In this study, we constructed prognostic immune profiles based on The Cancer Genome Atlas (TCGA)-PRAD data sets and tested their predictive power on total and internal data sets. Then, we looked at how the lymphocyte of tumor invasion varied between the high-risk group and the low-risk group. Five immune-related genes made up the immune marker, which was an independent predictive factor in patients with PRAD. Patients in the low-risk score group had a higher rate of overall survival and a stronger infiltration of immune cells in the tumor microenvironment, which was highly related to clinical outcomes but required prospective validation.

Prostate cancer; Tumor immune microenvironment; Immune checkpoint inhibitor; Immunotherapy; Prognostic model

[1] Jiang T, Guo J, Hu Z, Zhao M, Gu Z, Miao S. Identification of potential prostate cancer-related pseudogenes based on competitive endogenous RNA network hypothesis. Medical Science Monitor. 2018; 24: 4213–4239.

[2] Wu Z, Ding Z, Cheng B, Cui Z. The inhibitory effect of human DEFA5 in growth of gastric cancer by targeting BMI1. Cancer Science. 2021; 112: 1075–1083.

[3] Ding Y, Wu H, Warden C, Steele L, Liu X, Iterson MV, et al. Gene expression differences in prostate cancers between young and old men. PLOS Genetics. 2016; 12: e1006477.

[4] Li B, Severson E, Pignon J, Zhao H, Li T, Novak J, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biology. 2016; 17: 174.

[5] Zhang B, Zhou YL, Chen X, Wang Z, Wang Q, Ju F, et al. Efficacy and safety of CTLA-4 inhibitors combined with PD-1 inhibitors or chemotherapy in patients with advanced melanoma. International Immunopharmacology. 2019; 68: 131–136.

[6] Ogata H, Goto S, Sato K, Fujibuchi W, Bono H, Kanehisa M. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Research. 1999; 27: 29–34.

[7] Walter W, Sánchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics. 2015; 31: 2912–2914.

[8] Chkaiban L, Tosi L, Parekkadan B. Assembly of long-adapter single-strand oligonucleotide (LASSO) probes for massively parallel capture of kilobase size DNA targets. Current Protocols. 2021; 1: e278.

[9] Nahm FS. Receiver operating characteristic curve: overview and practical use for clinicians. Korean Journal of Anesthesiology. 2022; 75: 25–36.

[10] Jin X, Xie H, Liu X, Shen Q, Wang Z, Hao H, et al. RELL1, a novel oncogene, accelerates tumor progression and regulates immune infiltrates in glioma. International Immunopharmacology. 2020; 87: 106707.

[11] Kim TJ, Koo KC. Current status and future perspectives of checkpoint inhibitor immunotherapy for prostate cancer: a comprehensive review. International Journal of Molecular Sciences. 2020; 21: 5484.

[12] Craven KE, Gökmen-Polar Y, Badve SS. CIBERSORT analysis of TCGA and METABRIC identifies subgroups with better outcomes in triple negative breast cancer. Scientific Reports. 2021; 11: 4691.

[13] Heagerty PJ, Zheng Y. Survival model predictive accuracy and ROC curves. Biometrics. 2005; 61: 92–105.

[14] Lu Z, Chen Y, Chen S, Zhu X, Wang C, Wang Z, et al. Comprehensive prognostic analysis of immune implication value and oxidative stress significance of NECAP2 in low-grade glioma. Oxidative Medicine and Cellular Longevity. 2022; 2022: 1–39.

[15] Ren S, Wang W, Shen H, Zhang C, Hao H, Sun M, et al. Development and validation of a clinical prognostic model based on immune-related genes expressed in clear cell renal cell carcinoma. Frontiers in Oncology. 2020; 10: 1496.

[16] Ge X, Wang Z, Jiang R, Ren S, Wang W, Wu B, et al. SCAMP4 is a novel prognostic marker and correlated with the tumor progression and immune infiltration in glioma. The International Journal of Biochemistry & Cell Biology. 2021; 139: 106054.

[17] Khosh Kish E, Choudhry M, Gamallat Y, Buharideen SM, DD, Bismar TA. The expression of proto-oncogene ETS-related gene (ERG) plays a central role in the oncogenic mechanism involved in the development and progression of prostate cancer. International Journal of Molecular Sciences. 2022; 23: 4772.

[18] Schöpf B, Weissensteiner H, Schäfer G, Fazzini F, Charoentong P, Naschberger A, et al. OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. Nature Communications. 2020; 11: 1487.

[19] Mehra R, Kumar-Sinha C, Shankar S, Lonigro RJ, Jing X, Philips NE, et al. Characterization of bone metastases from rapid autopsies of prostate cancer patients. Clinical Cancer Research. 2011; 17: 3924–3932.

[20] Makino Y, Kamiyama Y, Brown JB, Tanaka T, Murakami R, Teramoto Y, et al. Comprehensive genomics in androgen receptor-dependent castration-resistant prostate cancer identifies an adaptation pathway mediated by opioid receptor kappa 1. Communications Biology. 2022; 5: 299.

[21] Shtivelman E, Beer TM, Evans CP. Molecular pathways and targets in prostate cancer. Oncotarget. 2014; 5: 7217–7259.

[22] Cochran M, East K, Greve V, Kelly M, Kelley W, Moore T, et al. A study of elective genome sequencing and pharmacogenetic testing in an unselected population. Molecular Genetics & Genomic Medicine. 2021; 9: e1766.

[23] Hernández-Llodrà S, Juanpere N, de Muga S, Lorenzo M, Gil J, Font-Tello A, et al. ERG overexpression plus SLC45A3 (prostein) and PTEN expression loss: strong association of the triple hit phenotype with an aggressive pathway of prostate cancer progression. Oncotarget. 2017; 8: 74106–74118.

[24] Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554: 544–548.

[25] Brackenier C, Kinget L, Cappuyns S, Verslype C, Beuselinck B, Dekervel J. Unraveling the synergy between atezolizumab and bevacizumab for the treatment of hepatocellular carcinoma. Cancers. 2023; 15: 348.

[26] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39: 1–10.

[27] Wang L, Yao Y, Xu C, Wang X, Wu D, Hong Z. Exploration of the tumor mutational burden as a prognostic biomarker and related hub gene identification in prostate cancer. Technology in Cancer Research & Treatment. 2021; 20: 15330338211052154.

[28] Lin D, Ettinger SL, Qu S, Xue H, Nabavi N, Chuen Choi SY, et al. Metabolic heterogeneity signature of primary treatment-naïve prostate cancer. Oncotarget. 2017; 8: 25928–25941.

[29] Sklavos MM, Zhou CK, Pinto LA, Cook MB. Prediagnostic circulating anti-Müllerian hormone concentrations are not associated with prostate cancer risk. Cancer Epidemiology, Biomarkers & Prevention. 2014; 23: 2597–2602.

[30] Chauvin M, Garambois V, Colombo PE, Chentouf M, Gros L, Brouillet JP, et al. Anti-Müllerian hormone (AMH) autocrine signaling promotes survival and proliferation of ovarian cancer cells. Scientific Reports. 2021; 11: 2231.

[31] Cao K, Jiang X, Wang B, Ni Z, Chen Y. SAA1 Expression as a potential prognostic marker of the tumor microenvironment in glioblastoma. Frontiers in Neurology. 2022; 13: 905561.

[32] Yajun C, Chen Y, Xiaosa L, Xiao W, Jia C, Zhong W, et al. Loss of Sun2 promotes the progression of prostate cancer by regulating fatty acid oxidation. Oncotarget. 2017; 8: 89620–89630.

[33] Zhang H, Xu Y, Deng G, Yuan F, Tan Y, Gao L, et al. SAA1 knockdown promotes the apoptosis of glioblastoma cells via downregulation of AKT signaling. Journal of Cancer. 2021; 12: 2756–2767.

[34] Ma JB, Bai JY, Zhang HB, Jia J, Shi Q, Yang C, et al. KLF5 inhibits STAT3 activity and tumor metastasis in prostate cancer by suppressing IGF1 transcription cooperatively with HDAC1. Cell Death & Disease. 2020; 11: 466.

[35] Samaržija I. Post-translational modifications that drive prostate cancer progression. Biomolecules. 2021; 11: 247.

[36] Mirzaei S, Paskeh MDA, Okina E, Gholami MH, Hushmandi K, Hashemi M, et al. Molecular landscape of LncRNAs in prostate cancer: a focus on pathways and therapeutic targets for intervention. Journal of Experimental & Clinical Cancer Research. 2022; 41: 214.

[37] Kim WK, Olson AW, Mi J, Wang J, Lee DH, Le V, et al. Aberrant androgen action in prostatic progenitor cells induces oncogenesis and tumor development through IGF1 and Wnt axes. Nature Communications. 2022; 13: 4364.

[38] Born J, Hendricks A, Hauser C, Egberts JH, Becker T, Röder C, et al. Detection of marker associated with CTC in colorectal cancer in mononuclear cells of patients with benign inflammatory intestinal diseases. Cancers. 2021; 14: 47.