Identification of an immune-related metabolic gene signature to predict possible prognosis in endometrial cancer and reveals immune landscape feature

The immunotherapy of endometrial cancer (EC) has gradually attracted attention and metabolic reprogramming is associate with tumor immune infiltration. Our goal was to use proteome analysis to examine the role of immune-related metabolic genes (IRMGs) in EC. Data-independent acquisition mass spectrometry (DIA-MS) was performed on 20 EC patients, consisting of 10 high-grade and 10 low-grade cancer tissues. IRMGs were screened using Spearman correlation, and an immune-related metabolic prognosis signature (IRMPS) was constructed based on the Cancer Genome Atlas-Uterine Corpus Endometrioid Carcinoma (TCGA-UCEC) cohort using the least absolute shrinkage and selection operator (LASSO) regression analysis. We also investigated differences between different risk groups in terms of prognostic value, clinical potency, immune characteristics and therapy response. In total, 285 differentially expressed genes (DEGs) were acquired via DIA-MS. Subsequently, metabolic-DEGs and immune-DEGs were analyzed by Spearman correlation to identify 41 IRMGs. Finally, seven IRMGs, including NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2 (NDUFA2), AMPK-alpha2 (PRKAA2), syntaxin binding protein 1 (STXBP1), NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9 (NDUFB9), ribosomal protein S27-like (RPS27L), lysolecithin acyltransferase 2 (LPCAT2) and uridine monophosphate synthetase (UMPS) were identified to establish a prognosis signature. The risk score was determined as an independent prognostic indicator, and patients in the IRMPS-high group was strong linked with adverse prognosis for EC. Additionally, IRMPS was closely related with tumor immune infiltration. Notably, the IRMPS-low group had better immune checkpoint inhibitors (ICI) treatment response and more sensitive to chemotherapy drugs. In conclusion, IRMPS can serve as a precise prognostic tool to guide the personalized treatment of EC patients.

Endometrial cancer; Immune; Metabolic; Immune infiltration; Immunotherapy; Prognostic signature

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2021; 71: 209–249.

[2] Oaknin A, Bosse TJ, Creutzberg CL, Giornelli G, Harter P, Joly F, et al. Endometrial cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2022; 33: 860–877.

[3] Shen Y, Yang W, Liu J, Zhang Y. Minimally invasive approaches for the early detection of endometrial cancer. Molecular Cancer. 2023; 22: 53.

[4] Safdar NS, Stasenko M, Selenica P, Martin AS, da Silva EM, Sebastiao APM, et al. Genomic determinants of early recurrences in low-stage, low-grade endometrioid endometrial carcinoma. Journal of the National Cancer Institute. 2022; 114: 1545–1548.

[5] Zou W, Green DR. Beggars banquet: metabolism in the tumor immune microenvironment and cancer therapy. Cell Metabolism. 2023; 35: 1101–1113.

[6] Bejarano L, Jordāo MJC, Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Discovery. 2021; 11: 933–959.

[7] Raggi C, Taddei ML, Rae C, Braconi C, Marra F. Metabolic reprogramming in cholangiocarcinoma. Journal of Hepatology. 2022; 77: 849–864.

[8] Zhao X, Li K, Chen M, Liu L. Metabolic codependencies in the tumor microenvironment and gastric cancer: difficulties and opportunities. Biomedicine & Pharmacotherapy. 2023; 162: 114601.

[9] Gonzalez MA, Lu DR, Yousefi M, Kroll A, Lo CH, Briseño CG, et al. Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages. Journal of Experimental Medicine. 2023; 220: e20221472.

[10] Zhou H, Zhang Y, Zhang R, Zhao M, Chen W, Liu Y, et al. A tumor-microenvironment-activatable molecular pro-theranostic agent for photodynamic and immunotherapy of cancer. Advanced Materials. 2023; 35: e2211485.

[11] Guo D, Ji X, Xie H, Ma J, Xu C, Zhou Y, et al. Targeted reprogramming of vitamin B3 metabolism as a nanotherapeutic strategy towards chemoresistant cancers. To be published in Advanced Materials. 2023.[Preprint]

[12] Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nature Reviews Drug Discovery. 2019; 18: 379–401.

[13] Li F, Huang C, Qiu L, Li P, Shi J, Zhang G. Comprehensive analysis of immune-related metabolic genes in lung adenocarcinoma. Frontiers in Endocrinology. 2022; 13: 894754.

[14] Miao YR, Zhang Q, Lei Q, Luo M, Xie GY, Wang H, et al. ImmuCellAI: a unique method for comprehensive T‐cell subsets abundance prediction and its application in cancer immunotherapy. Advanced Science. 2020; 7: 1902880.

[15] van Weelden WJ, Lalisang RI, Bulten J, Lindemann K, van Beekhuizen HJ, Trum H, et al. Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer. American Journal of Obstetrics and Gynecology. 2021; 225: 407.e1–407. e16.

[16] He Y, Shi Y, Yang Y, Huang H, Feng Y, Wang Y, et al. Chrysin induces autophagy through the inactivation of the ROS‑mediated Akt/mTOR signaling pathway in endometrial cancer. International Journal of Molecular Medicine. 2021; 48: 172.

[17] Zheng P, Lin Z, Ding Y, Duan S. Targeting the dynamics of cancer metabolism in the era of precision oncology. Metabolism. 2023; 145: 155615.

[18] Tan YQ, Zhang X, Zhang S, Zhu T, Garg M, Lobie PE, et al. Mitochondria: the metabolic switch of cellular oncogenic transformation. Biochimica et Biophysica Acta—Reviews on Cancer. 2021; 1876: 188534.

[19] Hortová-Kohoutková M, Lázničková P, Frič J. How immune-cell fate and function are determined by metabolic pathway choice: the bioenergetics underlying the immune response. BioEssays. 2021; 43: e2000067.

[20] Wang Z, Chen H, Xue L, He W, Shu W, Wu H, et al. High throughput proteomic and metabolic profiling identified target correction of metabolic abnormalities as a novel therapeutic approach in head and neck paraganglioma. Translational Oncology. 2021; 14: 101146.

[21] Shi Y, Zhuang Y, Zhang J, Chen M, Wu S. Identification of tumorigenic and prognostic biomarkers in colorectal cancer based on microRNA expression profiles. BioMed Research International. 2020; 2020: 7136049.

[22] Li LD, Sun HF, Liu XX, Gao SP, Jiang HL, Hu X, et al. Down-regulation of NDUFB9 promotes breast cancer cell proliferation, metastasis by mediating mitochondrial metabolism. PLOS ONE. 2015; 10: e0144441.

[23] Choi S, Ha M, Lee JS, Heo HJ, Kim GH, Oh SO, et al. Novel prognostic factor for uveal melanoma: bioinformatics analysis of three independent cohorts. Anticancer Research. 2020; 40: 3839–3846.

[24] Uchikado Y, Inoue H, Haraguchi N, Mimori K, Natsugoe S, Okumura H, et al. Gene expression profiling of lymph node metastasis by oligomicroarray analysis using laser microdissection in esophageal squamous cell carcinoma. International Journal of Oncology. 2006; 29: 1337–1347.

[25] Weijiao Y, Fuchun L, Mengjie C, Xiaoqing Q, Hao L, Yuan L, et al. Immune infiltration and a ferroptosis-associated gene signature for predicting the prognosis of patients with endometrial cancer. Aging. 2021; 13: 16713–16732.

[26] Zhang Q, Hong Z, Zhu J, Zeng C, Tang Z, Wang W, et al. miR-4999-5p predicts colorectal cancer survival outcome and reprograms glucose metabolism by targeting PRKAA2. OncoTargets and Therapy. 2020; 13: 1199–1210.

[27] Lu Z, He S, Jiang J, Zhuang L, Wang Y, Yang G, et al. Base-edited cynomolgus monkeys mimic core symptoms of STXBP1 encephalopathy. Molecular Therapy. 2022; 30: 2163–2175.

[28] Wang X, Fu G, Wen J, Chen H, Zhang B, Zhu D. Membrane location of syntaxin-binding protein 1 is correlated with poor prognosis of lung adenocarcinoma. The Tohoku Journal of Experimental Medicine. 2020; 250: 263–270.

[29] Yu M, Tian Y, Wu M, Gao J, Wang Y, Liu F, et al. A comparison of mRNA and circRNA expression between squamous cell carcinoma and adenocarcinoma of the lungs. Genetics and Molecular Biology. 2020; 43: e20200054.

[30] Xu AF, Molinuevo R, Fazzari E, Tom H, Zhang Z, Menendez J, et al. Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs Rps27 and Rps27l in vertebrates. eLife. 2023; 12: e78695.

[31] Xiong X, Liu X, Li H, He H, Sun Y, Zhao Y. Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis. Cell Death & Disease. 2018; 9: 1131.

[32] Huang CJ, Yang SH, Lee CL, Cheng YC, Tai SY, Chien CC. Ribosomal protein S27-like in colorectal cancer: a candidate for predicting prognoses. PLOS ONE. 2013; 8: e67043.

[33] Sun S, He H, Ma Y, Xu J, Chen G, Sun Y, et al. Inactivation of ribosomal protein S27-like impairs DNA interstrand cross-link repair by destabilization of FANCD2 and FANCI. Cell Death & Disease. 2020; 11: 852.

[34] Agarwal AK, Garg A. Enzymatic activity of the human 1-acylglycerol-3- phosphate-O-acyltransferase isoform 11: upregulated in breast and cervical cancers. Journal of Lipid Research. 2010; 51: 2143–2152.

[35] Souza JL, Martins-Cardoso K, Guimarães IS, de Melo AC, Lopes AH, Monteiro RQ, et al. Interplay between EGFR and the platelet-activating factor/PAF receptor signaling axis mediates aggressive behavior of cervical cancer. Frontiers in Oncology. 2020; 10: 557280.

[36] Yu S, Li Z, Tu L, Pu Y, Yan D, Wang X, et al. Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis. Journal of Physiology and Biochemistry. 2022; 78: 679–687.

[37] Niu Y, Fan X, Wang Y, Lin J, Hua L, Li X, et al. Genome-wide CRISPR screening reveals pyrimidine metabolic reprogramming in 5-FU chronochemotherapy of colorectal cancer. Frontiers in Oncology. 2022; 12: 949715.

[38] Luo L, Zhang J, Tang H, Zhai D, Huang D, Ling L, et al. LncRNA SNORD3A specifically sensitizes breast cancer cells to 5-FU by sponging miR-185-5p to enhance UMPS expression. Cell Death & Disease. 2020; 11: 329.

[39] Yin L, He N, Chen C, Zhang N, Lin Y, Xia Q. Identification of novel blood-based HCC-specific diagnostic biomarkers for human hepatocellu-lar carcinoma. Artificial Cells, Nanomedicine, and Biotechnology. 2019; 47: 1908–1916.

[40] Zhang Y, Zhao W, Na F, Li M, Tong S. LINC01354/microRNA-216b/KRAS axis promotes the occurrence and metastasis of endometrial cancer. Nanoscale Research Letters. 2022; 17: 21.

[41] Borys F, Tobiasz P, Poterała M, Fabczak H, Krawczyk H, Joachimiak E. Systematic studies on anti-cancer evaluation of stilbene and dibenzo[b,f ]oxepine derivatives. Molecules. 2023; 28: 3558.

[42] Bucher N, Britten CD. G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. British Journal of Cancer. 2008; 98: 523–528.

[43] Yang Y, Lu T, Jia X, Gao Y. FSTL1 suppresses triple-negative breast cancer lung metastasis by inhibiting M2-like tumor-associated macrophage recruitment toward the lungs. Diagnostics. 2023; 13: 1724.

[44] Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B- cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. Journal of Clinical Oncology. 2015; 33: 540–549.

[45] Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. Journal of Experimental Medicine. 2013; 210: 1695–1710.

[46] Vignali PDA, DePeaux K, Watson MJ, Ye C, Ford BR, Lontos K, et al. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nature Immunology. 2023; 24: 267–279.

[47] Mathew AA, Zakkariya ZT, Ashokan A, Manohar M, Keechilat P, Nair SV, et al. 5-FU mediated depletion of myeloid suppressor cells enhances T- cell infiltration and anti-tumor response in immunotherapy-resistant lung tumor. International Immunopharmacology. 2023; 120: 110129.

[48] Bonazzi VF, Kondrashova O, Smith D, Nones K, Sengal AT, Ju R, et al. Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer. Genome Medicine. 2022; 14: 3.

[49] Dai Y, Zhao L, Hua D, Cui L, Zhang X, Kang N, et al. Tumor immune microenvironment in endometrial cancer of different molecular subtypes: evidence from a retrospective observational study. Frontiers in Immunology. 2022; 13: 1035616.

[50] Oaknin A, Gilbert L, Tinker AV, Brown J, Mathews C, Press J, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET—a phase I, single-arm study. Journal for ImmunoTherapy of Cancer. 2022; 10: e003777.

[51] Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. Journal of Clinical Oncology. 2020; 38: 1–10.