The lactylation index predicts the immune microenvironment and prognosis of pan-cancer patients
), SHICANG YU2,3,4,5()Abstract
Protein lactylation is a new way for the “metabolic waste” lactic acid to perform novel functions. Nevertheless, our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited. The construction of a scoring system for lactylation to predict the prognosis of pan-cancer patients and to evaluate the tumor immune microenvironment (TIME) would improve our understanding of the clinical significance of lactylation.
Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma (PAAD) patients. Subsequently, a scoring system was developed using the least absolute shrinkage and selection operator (LASSO) regression. Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system. Finally, leucine rich repeat containing 1 (LRRC1), a newly discovered lactylation-related gene, was analyzed in PAAD in vitro.
Utilizing the profiles of 332 lactylation-related genes, a total of 177 patients with PAAD were segregated into two distinct groups. LacClusterhigh patients had a poorer prognosis than LacClusterlow patients. Through the differential analysis between the LacClusterhigh and LacClusterlow groups, we identified additional genes associated with lactylation. These genes were then integrated to construct the LacCluster-enhanced system, which enabled more accurate prognosis prediction for patients with PAAD. Then, a lactylation index containing three genes (LacI-3) was constructed using LASSO regression. This was done to enhance the usability of the LacCluster-enhanced system in the clinic. Compared to those in the LacI-3high subgroup, patients in the LacI-3low subgroup exhibited increased expression of immune checkpoint-related genes, more immune cell infiltration, lower tumor mutation burdens, and better prognoses, indicating a “hot tumor” phenotype. Moreover, knocking down the expression of LRRC1, the hub gene in the LacI-3 scoring system, inhibited PAAD cell invasion, migration, and proliferation in vitro. Ultimately, the significance of LacI-3 across cancers was confirmed.
Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.
Electronic Supplementary Material
References
Jiang X, He J, Wang Y, Liu J, Li X, He X, et al. A pan-cancer analysis of the biological function and clinical value of BTLA in tumors. BIOCELL. 2023;47(2):351–66. doi:10.32604/biocell.2023.025157.
Lv B, Wang Y, Ma D, Cheng W, Liu J, Yong T, et al. Immunotherapy: reshape the tumor immune microenvironment. Front Immunol. 2022;13:844142. doi:10.3389/fimmu.2022.844142.
Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N, et al. The cancer metabolic reprogramming and immune response. Mol Cancer. 2021;20(1):28. doi:10.1186/s12943-021-01316-8.
Terry S, Engelsen AST, Buart S, Elsayed WS, Venkatesh GH, Chouaib S. Hypoxia-driven intratumor heterogeneity and immune evasion. Cancer Lett. 2020;492:1–10. doi:10.1016/j.canlet.2020.07.004.
Karayama M, Masuda J, Mori K, Yasui H, Hozumi H, Suzuki Y, et al. Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer. Clin Transl Oncol. 2021;23(2):418–23. doi:10.1007/s12094-020-02421-8.
Huang B, Song BL, Xu C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab. 2020; 2(2):132–41. doi:10.1038/s42255-020-0174-0.
Chen B, Gao A, Tu B, Wang Y, Yu X, Wang Y, et al. Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery. Biomaterials. 2020;255:120187. doi:10.1016/j.biomaterials.2020.120187.
Wang Z, Jiang Q, Dong C. Metabolic reprogramming in triple-negative breast cancer. Cancer Biol Med. 2020;17(1):44–59. doi:10.20892/j.issn.2095-3941.2019.0210.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.
Böttcher M, Baur R, Stoll A, Mackensen A, Mougiakakos D. Linking immunoevasion and metabolic reprogramming in B-cell-derived lymphomas. Front Oncol. 2020;10:594782. doi:10.3389/fonc.2020.594782.
Moreno-Yruela C, Zhang D, Wei W, Bæk M, Liu W, Gao J, et al. Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. Sci Adv. 2022;8(3):eabi6696. doi:10.1126/sciadv.abi6696.
Wan N, Wang N, Yu S, Zhang H, Tang S, Wang D, et al. Cyclic immonium ion of lactyllysine reveals widespread lactylation in the human proteome. Nat Methods. 2022;19(7):854–64. doi:10.1038/s41592-022-01523-1.
Cheng Z, Huang H, Li M, Liang X, Tan Y, Chen Y. Lactylation-related gene signature effectively predicts prognosis and treatment responsiveness in hepatocellular carcinoma. Pharmaceuticals. 2023;16(5):644. doi:10.3390/ph16050644.
Aran D. Cell-type enrichment analysis of bulk transcriptomes using xCell. Methods Mol Biol. 2020;2120:263–76. doi:10.1007/978-1-0716-0327-7.
Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 2017;18(1):248–62. doi:10.1016/j.celrep.2016.12.019.
He Y, Jiang Z, Chen C, Wang X. Classification of triple-negative breast cancers based on Immunogenomic profiling. J Exp Clin Cancer Res. 2018;37(1):327. doi:10.1186/s13046-018-1002-1.
Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612. doi:10.1038/ncomms3612.
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7. doi:10.1038/nmeth.3337.
Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell. 2021;39(2):154–73. doi:10.1016/j.ccell.2020.10.001.
Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012;149(3):656–70. doi:10.1016/j.cell.2012.01.058.
Guillaumond F, Leca J, Olivares O, Lavaut MN, Vidal N, Berthezène P, et al. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc Natl Acad Sci U S A. 2013;110(10):3919–24. doi:10.1073/pnas.1219555110.
Zhao D, Zou SW, Liu Y, Zhou X, Mo Y, Wang P, et al. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell. 2013;23(4):464–76. doi:10.1016/j.ccr.2013.02.005.
Lv X, Lv Y, Dai X. Lactate, histone lactylation and cancer hallmarks. Expert Rev Mol Med. 2023;25:e7. doi:10.1017/erm.2022.42.
Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X, et al. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 2021;22(1):85. doi:10.1186/s13059-021-02308-z.
Jin M, Cao W, Chen B, Xiong M, Cao G. Tumor-derived lactate creates a favorable niche for tumor via supplying energy source for tumor and modulating the tumor microenvironment. Front Cell Dev Biol. 2022;10:808859. doi:10.3389/fcell.2022.808859.
Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019;18(3):197–218. doi:10.1038/s41573-018-0007-y.
Navarro F, Casares N, Martín-Otal C, Lasarte-Cía A, Gorraiz M, Sarrión P, et al. Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy. Oncoimmunology. 2022;11(1):2070337. doi:10.1080/2162402X.2022.2070337.
Lee MY, Jeon JW, Sievers C, Allen CT. Antigen processing and presentation in cancer immunotherapy. J Immunother Cancer. 2020;8(2):e001111 doi:10.1136/jitc-2020-001111.
Wu S, Zhang H, Gao C, Chen J, Li H, Meng Z, et al. Hyperglycemia enhances immunosuppression and aerobic glycolysis of pancreatic cancer through upregulating Bmi1-UPF1-HK2 pathway. Cell Mol Gastroenterol Hepatol. 2022; 14(5):1146–65. doi:10.1016/j.jcmgh.2022.07.008.
Lawlor RT, Mattiolo P, Mafficini A, Hong SM, Piredda ML, Taormina SV, et al. Tumor mutational burden as a potential biomarker for immunotherapy in pancreatic cancer: systematic review and still-open questions. Cancers. 2021;13(13):3119. doi:10.3390/cancers13133119.
Kciuk M, Gielecińska A, Mujwar S, Kołat D, Kałuzińska-Kołat Ż, Celik I, et al. Doxorubicin-an agent with multiple mechanisms of anticancer activity. Cells. 2023;12(4):659. doi:10.3390/cells12040659.
Voorwerk L, Slagter M, Horlings HM, Sikorska K, van de Vijver KK, de Maaker M, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med. 2019;25(6):920–8. doi:10.1038/s41591-019-0432-4.
Emami F, Banstola A, Vatanara A, Lee S, Kim JO, Jeong JH, et al. Doxorubicin and Anti-PD-L1 antibody conjugated gold nanoparticles for colorectal cancer photochemotherapy. Mol Pharm. 2019;16(3):1184–99. doi:10.1021/acs.molpharmaceut.8b01157.
京公网安备11010802044758号