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Original Research

CD39+ conventional CD4+ T cells with exhaustion traits and cytotoxic potential infiltrate tumors and expand upon CTLA-4 blockade

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Article: 2246319 | Received 31 Jan 2023, Accepted 05 Aug 2023, Published online: 18 Aug 2023

References

  • Borst J, Ahrends T, Babala N, Melief CJM, Kastenmüller W. CD4(+) T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18(10):635–16. doi:10.1038/s41577-018-0044-0.
  • Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H. The central role of CD4(+) T cells in the antitumor immune response. J Exp Med. 1998;188(12):2357–2368. doi:10.1084/jem.188.12.2357.
  • Sallusto F, Lanzavecchia A. Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. Eur J Immunol. 2009;39(8):2076–2082. doi:10.1002/eji.200939722.
  • Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. doi:10.1038/nrc3245.
  • Takeuchi A, Saito T. CD4 CTL, a cytotoxic subset of CD4(+) T cells, their differentiation and function. Front Immunol. 2017;8:194. doi:10.3389/fimmu.2017.00194.
  • Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, Blasberg R, Yagita H, Muranski P, Antony PA, et al. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med. 2010;207(3):637–650. doi:10.1084/jem.20091918.
  • Kitano S, Tsuji T, Liu C, Hirschhorn-Cymerman D, Kyi C, Mu Z, Allison JP, Gnjatic S, Yuan JD, Wolchok JD, et al. Enhancement of tumor-reactive cytotoxic CD4+ T cell responses after ipilimumab treatment in four advanced melanoma patients. Cancer Immunol Res. 2013;1(4):235–244. doi:10.1158/2326-6066.CIR-13-0068.
  • Li S, Zhuang S, Heit A, Koo S-L, Tan AC, Chow I-T, Kwok WW, Tan IB, Tan DSW, Simoni Y, et al. Bystander CD4 + T cells infiltrate human tumors and are phenotypically distinct. Oncoimmunology. 2022;11(1):2012961. doi:10.1080/2162402X.2021.2012961.
  • Poncette L, Bluhm J, Blankenstein T. The role of CD4 T cells in rejection of solid tumors. Curr Opin Immunol. 2022;74:18–24. doi:10.1016/j.coi.2021.09.005.
  • Baitsch L, Baumgaertner P, Devevre E, Raghav SK, Legat A, Barba L, Wieckowski S, Bouzourene H, Deplancke B, Romero P, et al. Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients. J Clin Invest. 2011;121(6):2350–2360. doi:10.1172/JCI46102.
  • Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DAA, Wherry EJ, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29–37. doi:10.1038/ni.1679.
  • Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–499. doi:10.1038/ni.2035.
  • Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, Werner MT, Huang AC, Alexander KA, Wu JE, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature. 2019;571(7764):211–218. doi:10.1038/s41586-019-1325-x.
  • McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019;37(1):457–495. doi:10.1146/annurev-immunol-041015-055318.
  • Canale FP, Ramello MC, Nunez N, Furlan CLA, Bossio SN, Serrán MG, Boari JT, Del Castillo A, Ledesma M, Sedlik C, et al. CD39 expression defines cell exhaustion in tumor-infiltrating CD8(+) T cells. Cancer Res. 2018;78(1):115–128. doi:10.1158/0008-5472.CAN-16-2684.
  • Duhen T, Duhen R, Montler R, Moses J, Moudgil T, de Miranda NF, Goodall CP, Blair TC, Fox BA, McDermott JE, et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun. 2018;9(1):2724. doi:10.1038/s41467-018-05072-0.
  • Balanca CC, Salvioni A, Scarlata CM, Michelas M, Martinez-Gomez C, Gomez-Roca C, Sarradin V, Tosolini M, Valle C, Pont F, et al. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells. JCI Insight. 2021;6(2). doi:10.1172/jci.insight.142513.
  • Kortekaas KE, Santegoets SJ, Sturm G, Ehsan I, van Egmond SL, Finotello F, Trajanoski Z, Welters MJP, van Poelgeest MIE, van der Burg SH, et al. CD39 identifies the CD4(+) tumor-specific T-cell population in human cancer. Cancer Immunol Res. 2020;8(10):1311–1321. doi:10.1158/2326-6066.CIR-20-0270.
  • Zacca ER, Amezcua Vesely MC, Ferrero PV, Acosta CDV, Ponce NE, Bossio SN, Mussano E, Onetti L, Cadile I, Acosta Rodríguez EV, et al. B cells from patients with rheumatoid arthritis show conserved CD39-mediated regulatory function and increased CD39 expression after positive response to therapy. J Mol Biol. 2021;433(1):166687. doi:10.1016/j.jmb.2020.10.021.
  • Ramello MC, Nunez NG, Tosello Boari J, Bossio SN, Canale FP, Abrate C, Ponce N, Del Castillo A, Ledesma M, Viel S, et al. Polyfunctional KLRG-1(+)CD57(+) Senescent CD4(+) T cells infiltrate tumors and are expanded in peripheral blood from breast cancer patients. Front Immunol. 2021;12:713132. doi:10.3389/fimmu.2021.713132.
  • Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. doi:10.1093/bioinformatics/bts635.
  • Weinstein JN, Collisson EA, Mills GB, Shaw KRM, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM. The cancer genome atlas pan-cancer analysis project. Nat Genet. 2013;45(10):1113–1120. doi:10.1038/ng.2764.
  • Wei L, Jin Z, Yang S, Xu Y, Zhu Y, Ji Y. TCGA-assembler 2: software pipeline for retrieval and processing of TCGA/CPTAC data. Bioinformatics. 2018;34(9):1615–1617. doi:10.1093/bioinformatics/btx812.
  • Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–140. doi:10.1093/bioinformatics/btp616.
  • Alboukadel K, Marcin K, Przemyslaw B. Survminer: Drawing survival Curves using “ggplot2”. 2021.
  • Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, Lynn RC, Philip M, Rao A, Restifo NP, et al. Defining ‘T cell exhaustion’. Nat Rev Immunol. 2019;19(11):665–674. doi:10.1038/s41577-019-0221-9.
  • Moretto MM, Hwang S, Khan IA. Downregulated IL-21 response and T follicular helper cell exhaustion correlate with compromised CD8 T cell immunity during chronic Toxoplasmosis. Front Immunol. 2017;8:1436. doi:10.3389/fimmu.2017.01436.
  • Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang NAAS, Andrews MC, Sharma P, Wang J, Wargo JA, Pe’er D, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell. 2017;170(6):1120–1133.e17. doi:10.1016/j.cell.2017.07.024.
  • Willsmore ZN, Coumbe BGT, Crescioli S, Reci S, Gupta A, Harris RJ, Chenoweth A, Chauhan J, Bax HJ, McCraw A, et al. Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action. Eur J Immunol. 2021;51(3):544–556. doi:10.1002/eji.202048747.
  • Miggelbrink AM, Jackson JD, Lorrey SJ, Srinivasan ES, Waibl-Polania J, Wilkinson DS, Fecci PE. CD4 T-Cell exhaustion: does it exist and what are its roles in cancer? Clin Cancer Res. 2021;27(21):5742–5752. doi:10.1158/1078-0432.CCR-21-0206.
  • Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva E, Chudakov D, Rudensky A. Regulatory T cells exhibit distinct features in human breast cancer. Immunity. 2016;45(5):1122–1134. doi:10.1016/j.immuni.2016.10.032.
  • Zheng C, Zheng L, Yoo JK, Guo H, Zhang Y, Guo X, Kang B, Hu R, Huang JY, Zhang Q, et al. Landscape of infiltrating T cells in Liver cancer revealed by single-cell sequencing. Cell. 2017;169(7):1342–1356.e16. doi:10.1016/j.cell.2017.05.035.
  • Zhang L, Yu X, Zheng L, Zhang Y, Li Y, Fang Q, Gao R, Kang B, Zhang Q, Huang JY, et al. Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature. 2018;564(7735):268–272. doi:10.1038/s41586-018-0694-x.
  • Guo X, Zhang Y, Zheng L, Zheng C, Song J, Zhang Q, Kang B, Liu Z, Jin L, Xing R, et al. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med. 2018;24(7):978–985. doi:10.1038/s41591-018-0045-3.
  • Veatch JR, Lee SM, Shasha C, Singhi N, Szeto JL, Moshiri AS, Kim TS, Smythe K, Kong P, Fitzgibbon M, et al. Neoantigen-specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function. Cancer Cell. 2022;40(4):393–409.e9. doi:10.1016/j.ccell.2022.03.006.
  • Link CL. Confidence intervals for the survival function using Cox’s proportional-hazard model with covariates. Biometrics. 1984;40(3):601–609. doi:10.2307/2530904.
  • Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen J-F, Enjyoji K, Linden J, Oukka M, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204(6):1257–1265. doi:10.1084/jem.20062512.
  • Schuler PJ, Schilling B, Harasymczuk M, Hoffmann TK, Johnson J, Lang S, Whiteside TL. Phenotypic and functional characteristics of CD4+ CD39+ FOXP3+ and CD4+ CD39+ FOXP3neg T-cell subsets in cancer patients. Eur J Immunol. 2012;42(7):1876–1885. doi:10.1002/eji.201142347.
  • Tondell A, Wahl SGF, Sponaas AM, Sørhaug S, Børset M, Haug M. Ectonucleotidase CD39 and checkpoint signalling receptor programmed death 1 are highly elevated in intratumoral immune cells in non–small-cell lung cancer. Transl Oncol. 2020;13(1):17–24. doi:10.1016/j.tranon.2019.09.003.
  • Salwe S, Singh A, Padwal V, Velhal S, Nagar V, Patil P, Deshpande A, Patel V. Immune signatures for HIV-1 and HIV-2 induced CD4(+)T cell dysregulation in an Indian cohort. BMC Infect Dis. 2019;19(1):135. doi:10.1186/s12879-019-3743-7.
  • Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20(3):326–336. doi:10.1038/s41590-019-0312-6.
  • Beltra JC, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, Casella V, Ngiow SF, Khan O, Huang YJ, et al. Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity. 2020;52(5):825–841.e8. doi:10.1016/j.immuni.2020.04.014.
  • Simoni Y, Becht E, Fehlings M, Loh CY, Koo S-L, Teng KWW, Yeong JPS, Nahar R, Zhang T, Kared H, et al. Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018;557(7706):575–579. doi:10.1038/s41586-018-0130-2.
  • Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, Liao P, Lang X, Kryczek I, Sell A, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569(7755):270–274. doi:10.1038/s41586-019-1170-y.
  • Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, Logothetis C, Sharma P. CTLA-4 blockade increases IFNγ-producing CD4 + ICOS hi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci U S A. 2008;105(39):14987–14992. doi:10.1073/pnas.0806075105.
  • Du W, Frankel TL, Green M, Zou W. IFNγ signaling integrity in colorectal cancer immunity and immunotherapy. Cell Mol Immunol. 2022;19(1):23–32. doi:10.1038/s41423-021-00735-3.
  • Zhang F, Bai H, Gao R, Fei K, Duan J, Zhang Z, Wang J, Hu X. Dynamics of peripheral T cell clones during PD-1 blockade in non-small cell lung cancer. Cancer Immunol Immunother. 2020;69(12):2599–2611. doi:10.1007/s00262-020-02642-4.
  • Bassez A, Vos H, Van Dyck L, Floris G, Arijs I, Desmedt C, Boeckx B, Vanden Bempt M, Nevelsteen I, Lambein K, et al. A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer. Nat Med. 2021;27(5):820–832. doi:10.1038/s41591-021-01323-8.
  • Savas P, Virassamy B, Ye C, Salim A, Mintoff CP, Caramia F, Salgado R, Byrne DJ, Teo ZL, Dushyanthen S, et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med. 2018;24(7):986–993. doi:10.1038/s41591-018-0078-7.
  • Laumont CM, Wouters MCA, Smazynski J, Gierc NS, Chavez EA, Chong LC, Thornton S, Milne K, Webb JR, Steidl C, et al. Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes coexpressing CD39, CD103, and PD-1 in ovarian cancer. Clin Cancer Res. 2021;27(14):4089–4100. doi:10.1158/1078-0432.CCR-20-4394.