Redox^high phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma

References

• Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–14. doi:10.3322/caac.21763.
   PubMed Web of Science ®Google Scholar
• de Castro G KI Jr., Wu YL, Wu Y-L, Lopes G, Kowalski DM, Turna HZ, Caglevic C, Zhang L, Karaszewska B, Laktionov KK. et al. Five-year outcomes with pembrolizumab versus chemotherapy as first-line therapy in patients with non–small-cell lung cancer and programmed death ligand-1 tumor proportion score ≥ 1% in the KEYNOTE-042 study. J Clin Oncol. 2023;41(11):1986–1991. doi:10.1200/JCO.21.02885.
   PubMed Web of Science ®Google Scholar
• Vesely MD, Zhang T, Chen L. Resistance mechanisms to anti-PD cancer immunotherapy. Annu Rev Immunol. 2022;40(1):45–74. doi:10.1146/annurev-immunol-070621-030155.
   PubMedGoogle Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi:10.1016/j.cell.2011.02.013.
   PubMed Web of Science ®Google Scholar
• Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, Jiang L, Ko B, Skelton R, Loudat L. et al. Metabolic heterogeneity in human lung tumors. Cell. 2016;164(4):681–694. doi:10.1016/j.cell.2015.12.034.
   PubMed Web of Science ®Google Scholar
• Han M, Bushong EA, Segawa M, Tiard A, Wong A, Brady MR, Momcilovic M, Wolf DM, Zhang R, Petcherski A. et al. Spatial mapping of mitochondrial networks and bioenergetics in lung cancer. Nature. 2023;615(7953):712–719. doi:10.1038/s41586-023-05793-3.
   PubMed Web of Science ®Google Scholar
• Kaymak I, Williams KS, Cantor JR, Jones RG. Immunometabolic interplay in the tumor microenvironment. Cancer Cell. 2021;39(1):28–37. doi:10.1016/j.ccell.2020.09.004.
   PubMed Web of Science ®Google Scholar
• Reinfeld BI, Madden MZ, Wolf MM, Chytil A, Bader JE, Patterson AR, Sugiura A, Cohen AS, Ali A, Do BT. et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature. 2021;593(7858):282–288. doi:10.1038/s41586-021-03442-1.
   PubMed Web of Science ®Google Scholar
• Lian G, Gnanaprakasam JR, Wang T, Wu R, Chen X, Liu L, Shen Y, Yang M, Yang J, Chen Y. et al. Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. Elife. 2018;7:e36158. doi:10.7554/eLife.36158.
   PubMed Web of Science ®Google Scholar
• Cheng J, Yan J, Liu Y, Shi J, Wang H, Zhou H, Zhou Y, Zhang T, Zhao L, Meng X. et al. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment. Cell Metab. 2023;35(6):961–978. doi:10.1016/j.cmet.2023.04.017.
   PubMed Web of Science ®Google Scholar
• Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453(7191):65–71. doi:10.1038/nature06880.
   PubMed Web of Science ®Google Scholar
• Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203. doi:10.1038/nature10491.
   PubMed Web of Science ®Google Scholar
• Joseph A, Juncheng P, Mondini M, Labaied N, Loi M, Adam J, Lafarge A, Astesana V, Obrist F, Klein C. et al. Metabolic features of cancer cells impact immunosurveillance. J Immunother Cancer. 2021;9(6):e002362. doi:10.1136/jitc-2021-002362.
   PubMed Web of Science ®Google Scholar
• Okayama H, Kohno T, Ishii Y, Shimada Y, Shiraishi K, Iwakawa R, Furuta K, Tsuta K, Shibata T, Yamamoto S. et al. Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. Cancer Res. 2012;72(1):100–111. doi:10.1158/0008-5472.CAN-11-1403.
   PubMed Web of Science ®Google Scholar
• Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC. et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–265. doi:10.1016/S0140-6736(16)32517-X.
   PubMed Web of Science ®Google Scholar
• Ravi A, Hellmann MD, Arniella MB, Holton M, Freeman SS, Naranbhai V, Stewart C, Leshchiner I, Kim J, Akiyama Y. et al. Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer. Nat Genet. 2023;55(5):807–819. doi:10.1038/s41588-023-01355-5.
   PubMed Web of Science ®Google Scholar
• Hu J, Zhang L, Xia H, Yan Y, Zhu X, Sun F, Sun L, Li S, Li D, Wang J. et al. Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing. Genome Med. 2023;15(1):14. doi:10.1186/s13073-023-01164-9.
   PubMed Web of Science ®Google Scholar
• Huang YF, Mohanty V, Dede M, Tsai K, Daher M, Li L, Rezvani K, Chen K. Characterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux. Nat Commun. 2023;14(1):4883. doi:10.1038/s41467-023-40457-w.
   PubMed Web of Science ®Google Scholar
• Luca BA, Steen CB, Matusiak M, Azizi A, Varma S, Zhu C, Przybyl J, Espín-Pérez A, Diehn M, Alizadeh AA. et al. Atlas of clinically distinct cell states and ecosystems across human solid tumors. Cell. 2021;184(21):5482–5496. doi:10.1016/j.cell.2021.09.014.
   PubMed Web of Science ®Google Scholar
• Miao YR, Zhang Q, Lei Q, Luo M, Xie G-Y, Wang H, Guo A-Y. ImmuCellAI: a unique method for comprehensive t-cell subsets abundance prediction and its application in cancer immunotherapy. Adv Sci (Weinh). 2020;7(7):1902880. doi:10.1002/advs.201902880.
   PubMedGoogle Scholar
• Yang L, He YT, Dong S, Wei X-W, Chen Z-H, Zhang B, Chen W-D, Yang X-R, Wang F, Shang X-M. et al. Single-cell transcriptome analysis revealed a suppressive tumor immune microenvironment in EGFR mutant lung adenocarcinoma. J Immunother Cancer. 2022;10(2):e003534. doi:10.1136/jitc-2021-003534.
   PubMed Web of Science ®Google Scholar
• Browaeys R, Saelens W, Saeys Y. NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods. 2020;17(2):159–162. doi:10.1038/s41592-019-0667-5.
   PubMed Web of Science ®Google Scholar
• Andreatta M, Corria-Osorio J, Muller S, Cubas R, Coukos G, Carmona SJ. Interpretation of T cell states from single-cell transcriptomics data using reference atlases. Nat Commun. 2021;12(1):2965. doi:10.1038/s41467-021-23324-4.
   PubMed Web of Science ®Google Scholar
• Miao TW, Yang DQ, Gao LJ, Yin J, Zhu Q, Liu J, He YQ, Chen X. Construction of a redox-related gene signature for overall survival prediction and immune infiltration in non-small-cell lung cancer. Front Mol Biosci. 2022;9:942402. doi:10.3389/fmolb.2022.942402.
   PubMed Web of Science ®Google Scholar
• Xiao L, Li Q, Huang Y, Fan Z, Ma L, Liu B, Yuan X. Construction of a redox-related prognostic model with predictive value in survival and therapeutic response for patients with lung adenocarcinoma. J Healthc Eng. 2022;2022:1–17. doi:10.1155/2022/7651758.
   Web of Science ®Google Scholar
• Peng HJ, Li XQ, Luan YC, Wang CJ, Wang W. A novel prognostic model related to oxidative stress for treatment prediction in lung adenocarcinoma. Front Oncol. 2023;13:1078697. doi:10.3389/fonc.2023.1078697.
   PubMed Web of Science ®Google Scholar
• Zhao C, Xiong KW, Bi D, Zhao FR, Lan YF, Jin XR, Li XP. Redox-associated messenger RNAs identify novel prognostic values and influence the tumor immune microenvironment of lung adenocarcinoma. Front Genet. 2023;14:1079035. doi:10.3389/fgene.2023.1079035.
   PubMed Web of Science ®Google Scholar
• Zavitsanou AM, Pillai R, Hao Y, Wu WL, Bartnicki E, Karakousi T, Rajalingam S, Herrera A, Karatza A, Rashidfarrokhi A. et al. KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance. Cell Rep. 2023;42(11):113295. doi:10.1016/j.celrep.2023.113295.
   PubMed Web of Science ®Google Scholar
• Ricciuti B, Arbour KC, Lin JJ, Vajdi A, Vokes N, Hong L, Zhang J, Tolstorukov MY, Li YY, Spurr LF. et al. Diminished efficacy of programmed death-(Ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status. J Thorac Oncol. 2022;17(3):399–410. doi:10.1016/j.jtho.2021.10.013.
   PubMed Web of Science ®Google Scholar
• Marinelli D, Mazzotta M, Scalera S, Terrenato I, Sperati F, D’Ambrosio L, Pallocca M, Corleone G, Krasniqi E, Pizzuti L. et al. KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden. Ann Oncol. 2020;31(12):1746–1754. doi:10.1016/j.annonc.2020.08.2105.
   PubMed Web of Science ®Google Scholar
• Zou W, Green DR. Beggars banquet: metabolism in the tumor immune microenvironment and cancer therapy. Cell Metab. 2023;35(7):1101–1113. doi:10.1016/j.cmet.2023.06.003.
   PubMed Web of Science ®Google Scholar
• Ge M, Papagiannakopoulos T, Bar-Peled L. Reductive stress in cancer: coming out of the shadows. Trends Cancer. 2023;10(2):103–112. doi:10.1016/j.trecan.2023.10.002.
   PubMed Web of Science ®Google Scholar
• Kim R, Hashimoto A, Markosyan N, Tyurin VA, Tyurina YY, Kar G, Fu S, Sehgal M, Garcia-Gerique L, Kossenkov A. et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature. 2022;612(7939):338–346. doi:10.1038/s41586-022-05443-0.
   PubMed Web of Science ®Google Scholar
• Satpathy S, Krug K, Jean Beltran PM, Savage SR, Petralia F, Kumar-Sinha C, Dou Y, Reva B, Kane MH, Avanessian SC. et al. A proteogenomic portrait of lung squamous cell carcinoma. Cell. 2021;184(16):4348–4371. doi:10.1016/j.cell.2021.07.016.
   PubMed Web of Science ®Google Scholar
• Li A, Wang Y, Yu Z, Tan Z, He L, Fu S, Shi M, Du W, Luo L, Li Z. et al. STK11/LKB1-deficient phenotype rather than mutation diminishes immunotherapy efficacy and represents STING/Type I interferon/CD8(+) T-Cell dysfunction in NSCLC. J Thorac Oncol. 2023;18(12):1714–1730. doi:10.1016/j.jtho.2023.07.020.
   PubMed Web of Science ®Google Scholar
• Arolt C, Dugan M, Wild R, Richartz V, Holz B, Scheel AH, Brägelmann J, Wagener-Ryczek S, Merkelbach-Bruse S, Wolf J. et al. KEAP1/NFE2L2 pathway signature outperforms KEAP1/NFE2L2 mutation status and reveals alternative pathway-activating mutations in NSCLC. J Thorac Oncol. 2023;18(11):1550–1567. doi:10.1016/j.jtho.2023.07.016.
   PubMed Web of Science ®Google Scholar
• Cai C, Cooper GF, Lu KN, Ma X, Xu S, Zhao Z, Chen X, Xue Y, Lee AV, Clark N. et al. Systematic discovery of the functional impact of somatic genome alterations in individual tumors through tumor-specific causal inference. PLOS Comput Biol. 2019;15(7):e1007088. doi:10.1371/journal.pcbi.1007088.
   PubMed Web of Science ®Google Scholar
• Li F, Han X, Li F, Wang R, Wang H, Gao Y, Wang X, Fang Z, Zhang W, Yao S. et al. LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response. Cancer Cell. 2015;27(5):698–711. doi:10.1016/j.ccell.2015.04.001.
   PubMed Web of Science ®Google Scholar
• Scalera S, Mazzotta M, Cortile C, Krasniqi E, Maria RD, Cappuzzo F, Ciliberto G, Maugeri-Saccà M. KEAP1-mutant NSCLC: the catastrophic failure of a cell-protecting hub. J Thorac Oncol. 2022;17(6):751–757. doi:10.1016/j.jtho.2022.03.011.
   PubMed Web of Science ®Google Scholar
• Roux C, Jafari SM, Shinde R, Duncan G, Cescon DW, Silvester J, Chu MF, Hodgson K, Berger T, Wakeham A. et al. Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1. Proc Natl Acad Sci U S A. 2019;116(10):4326–4335. doi:10.1073/pnas.1819473116.
   PubMed Web of Science ®Google Scholar
• Dan L, Liu L, Sun Y, Song J, Yin Q, Zhang G, Qi F, Hu Z, Yang Z, Zhou Z. et al. The phosphatase PAC1 acts as a T cell suppressor and attenuates host antitumor immunity. Nat Immunol. 2020;21(3):287–297. doi:10.1038/s41590-019-0577-9.
   PubMed Web of Science ®Google Scholar
• Corgnac S, Malenica I, Mezquita L, Auclin E, Voilin E, Kacher J, Halse H, Grynszpan L, Signolle N, Dayris T. et al. CD103(+)CD8(+) T(RM) cells accumulate in tumors of anti-PD-1-responder lung cancer patients and are tumor-reactive lymphocytes enriched with Tc17. Cell Rep Med. 2020;1(7):100127. doi:10.1016/j.xcrm.2020.100127.
   PubMedGoogle Scholar
• He Z, Khatib AM, Creemers JWM. The proprotein convertase furin in cancer: more than an oncogene. Oncogene. 2022;41(9):1252–1262. doi:10.1038/s41388-021-02175-9.
   PubMed Web of Science ®Google Scholar
• Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, Andersson J, Shevach EM, Quezado M, Bouladoux N. et al. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature. 2008;455(7210):246–250. doi:10.1038/nature07210.
   PubMed Web of Science ®Google Scholar
• Ojanen MJT, Caro FM, Aittomaki S, Ploquin MJ, Ortutay Z, Pekkarinen M, Kesseli J, Vähätupa M, Määttä J, Nykter M. et al. FURIN regulates cytotoxic T-lymphocyte effector function and memory cell transition in mice. Eur J Immunol. 2023;53(6):e2250246. doi:10.1002/eji.202250246.
   PubMed Web of Science ®Google Scholar
• Liu JY, Li F, Wang LP, Chen XF, Wang D, Cao L, Ping Y, Zhao S, Li B, Thorne SH. et al. CTL- vs Treg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. Br J Cancer. 2015;113(5):747–755. doi:10.1038/bjc.2015.290.
   PubMed Web of Science ®Google Scholar