Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
15 Feb 2024
15 Feb 2024
Historique:
received:
16
05
2023
accepted:
01
02
2024
revised:
19
12
2023
medline:
16
2
2024
pubmed:
16
2
2024
entrez:
15
2
2024
Statut:
epublish
Résumé
The tumor microenvironment (TME) plays a central role in the pathogenesis of chronic lymphocytic leukemia (CLL), contributing to disease progression and chemoresistance. Leukemic cells shape the TME into a pro-survival and immunosuppressive niche through contact-dependent and contact-independent interactions with the cellular components of the TME. Immune synapse (IS) formation is defective in CLL. Here we asked whether soluble factors released by CLL cells contribute to their protection from cytotoxic T cell (CTL)-mediated killing by interfering with this process. We found that healthy CTLs cultured in media conditioned by leukemic cells from CLL patients or Eμ-TCL1 mice upregulate the exhaustion marker PD-1 and become unable to form functional ISs and kill target cells. These defects were more pronounced when media were conditioned by leukemic cells lacking p66Shc, a proapoptotic adapter whose deficiency has been implicated in disease aggressiveness both in CLL and in the Eμ-TCL1 mouse model. Multiplex ELISA assays showed that leukemic cells from Eμ-TCL1 mice secrete abnormally elevated amounts of CCL22, CCL24, IL-9 and IL-10, which are further upregulated in the absence of p66Shc. Among these, IL-9 and IL-10 were also overexpressed in leukemic cells from CLL patients, where they inversely correlated with residual p66Shc. Using neutralizing antibodies or the recombinant cytokines we show that IL-9, but not IL-10, mediates both the enhancement in PD-1 expression and the suppression of effector functions in healthy CTLs. Our results demonstrate that IL-9 secreted by leukemic cells negatively modulates the anti-tumor immune abilities of CTLs, highlighting a new suppressive mechanism and a novel potential therapeutical target in CLL.
Identifiants
pubmed: 38360867
doi: 10.1038/s41419-024-06528-6
pii: 10.1038/s41419-024-06528-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
144Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG-20148
Organisme : Regione Toscana (Tuscany Region)
ID : Precise-CLL
Informations de copyright
© 2024. The Author(s).
Références
Capitani N, Patrussi L, Baldari CT. Nature vs. nurture: the two opposing behaviors of cytotoxic T lymphocytes in the tumor microenvironment. Int J Mol Sci. 2021;22:11221.
pubmed: 34681881
pmcid: 8540886
doi: 10.3390/ijms222011221
ten Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment. Biochim Biophys Acta Mol Cell Res. 2016;1863:401–13.
doi: 10.1016/j.bbamcr.2015.07.009
Ramsay AG, Johnson AJ, Lee AM, Gorgün G, Le Dieu R, Blum W, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Investig. 2008;118:2427–37.
pubmed: 18551193
pmcid: 2423865
Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121:1612–21.
pubmed: 23247726
pmcid: 3587324
doi: 10.1182/blood-2012-09-457531
Farhood B, Najafi M, Mortezaee K. CD8 + cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol. 2019;234:8509–21.
pubmed: 30520029
doi: 10.1002/jcp.27782
Cassioli C, Baldari CT. Lymphocyte polarization during immune synapse assembly: centrosomal actin joins the game. Front Immunol. 2022;13:830835.
pubmed: 35222415
pmcid: 8873515
doi: 10.3389/fimmu.2022.830835
Burger JA, Gribben JG. The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: Insight into disease biology and new targeted therapies. Semin Cancer Biol. 2014;24:71–81.
pubmed: 24018164
doi: 10.1016/j.semcancer.2013.08.011
Cassioli C, Patrussi L, Valitutti S, Baldari CT. Learning from TCR signaling and immunological synapse assembly to build new chimeric antigen receptors (CARs). Int J Mol Sci. 2022;23:14255.
pubmed: 36430728
pmcid: 9694822
doi: 10.3390/ijms232214255
Fooksman DR, Vardhana S, Vasiliver-Shamis G, Liese J, Blair DA, Waite J, et al. Functional anatomy of T cell activation and synapse formation. Annu Rev Immunol. 2010;28:79–105.
pubmed: 19968559
pmcid: 2885351
doi: 10.1146/annurev-immunol-030409-101308
Alarcón B, Mestre D, Martínez-Martín N. The immunological synapse: a cause or consequence of T-cell receptor triggering? Immunology. 2011;133:420–5.
pubmed: 21631496
pmcid: 3143353
doi: 10.1111/j.1365-2567.2011.03458.x
Dustin ML, Choudhuri K. Signaling and polarized communication across the T cell immunological synapse. Annu Rev Cell Dev Biol. 2016;32:303–25.
pubmed: 27501450
doi: 10.1146/annurev-cellbio-100814-125330
Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012;120:1412–21.
pubmed: 22547582
pmcid: 3423779
doi: 10.1182/blood-2012-02-411678
Allegra A, Musolino C, Tonacci A, Pioggia G, Casciaro M, Gangemi S. Clinico-biological implications of modified levels of cytokines in chronic lymphocytic leukemia: a possible therapeutic role. Cancers. 2020;12:524.
pubmed: 32102441
pmcid: 7072434
doi: 10.3390/cancers12020524
Shalapour S, Karin M. Pas de Deux: control of anti-tumor immunity by cancer-associated inflammation. Immunity. 2019;51:15–26.
pubmed: 31315033
pmcid: 6640850
doi: 10.1016/j.immuni.2019.06.021
Patrussi L, Capitani N, Baldari CT. Interleukin (IL)-9 supports the tumor-promoting environment of chronic lymphocytic leukemia. Cancers. 2021;13:6301.
pubmed: 34944921
pmcid: 8699356
doi: 10.3390/cancers13246301
Forconi F, Moss P. Perturbation of the normal immune system in patients with CLL. Blood. 2015;126:573–81.
pubmed: 26084672
doi: 10.1182/blood-2015-03-567388
Patrussi L, Manganaro N, Capitani N, Ulivieri C, Tatangelo V, Libonati F, et al. Enhanced IL-9 secretion by p66Shc-deficient CLL cells modulates the chemokine landscape of the stromal microenvironment. Blood. 2021;137:2182–95.
pubmed: 33181836
doi: 10.1182/blood.2020005785
Onnis A, Andreano E, Cassioli C, Finetti F, Della Bella C, Staufer O, et al. SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly. J Exp Med. 2023;220:e20220906.
pubmed: 36378226
doi: 10.1084/jem.20220906
Arasanz H, Gato-Cañas M, Zuazo M, Ibañez-Vea M, Breckpot K, Kochan G, et al. PD1 signal transduction pathways in T cells. Oncotarget. 2017;8:51936.
pubmed: 28881701
pmcid: 5584302
doi: 10.18632/oncotarget.17232
Capitani N, Lucherini OM, Sozzi E, Ferro M, Giommoni N, Finetti F, et al. Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia. Blood. 2010;115:3726–36.
pubmed: 20061561
doi: 10.1182/blood-2009-08-239244
Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005;122:221–33.
pubmed: 16051147
doi: 10.1016/j.cell.2005.05.011
Finetti F, Savino MT, Baldari CT. Positive and negative regulation of antigen receptor signaling by the Shc family of protein adapters. Immunol Rev. 2009;232:115–34.
pubmed: 19909360
doi: 10.1111/j.1600-065X.2009.00826.x
McClanahan F, Riches JC, Miller S, Day WP, Kotsiou E, Neuberg D, et al. Mechanisms of PD-L1/PD-1 mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eμ-TCL1 CLL mouse model. Blood. 2015;126:212–21.
pubmed: 25979947
pmcid: 4497962
doi: 10.1182/blood-2015-02-626754
Bichi R, Shinton SA, Martin ES, Koval A, Calin GA, Cesari R, et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci USA. 2002;99:6955–60.
pubmed: 12011454
pmcid: 124510
doi: 10.1073/pnas.102181599
Patrussi L, Capitani N, Ulivieri C, Manganaro N, Granai M, Cattaneo F, et al. p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape. Haematologica. 2019;104:2040–52.
pubmed: 30819907
pmcid: 6886430
doi: 10.3324/haematol.2018.209981
Finetti F, Capitani N, Manganaro N, Tatangelo V, Libonati F, Panattoni G, et al. Optimization of organotypic cultures of mouse spleen for staining and functional assays. Front Immunol. 2020;11:471.
pubmed: 32265925
pmcid: 7105700
doi: 10.3389/fimmu.2020.00471
Patrussi L, Capitani N, Baldari CT. P66Shc: a pleiotropic regulator of B cell trafficking and a gatekeeper in chronic lymphocytic leukemia. Cancers. 2020;12:1006.
pubmed: 32325830
pmcid: 7226591
doi: 10.3390/cancers12041006
Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Investig. 2017;127:3052–64.
pubmed: 28714866
pmcid: 5531425
doi: 10.1172/JCI89756
Kondo K, Shaim H, Thompson PA, Burger JA, Keating M, Estrov Z, et al. Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia. 2018;32:960–70.
pubmed: 28972595
doi: 10.1038/leu.2017.304
Chen N, Feng L, Qu H, Lu K, Li P, Lv X, et al. Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia. Oncol Rep. 2018;39:3064–72.
pubmed: 29658610
Abbassy HA, Aboelwafa RA, Ghallab OM. Evaluation of interleukin-9 expression as a potential therapeutic target in chronic lymphocytic leukemia in a cohort of egyptian patients. Indian J Hematol Blood Transfus. 2017;33:477–82.
pubmed: 29075057
pmcid: 5640552
doi: 10.1007/s12288-017-0804-1
Chen N, Lu K, Li P, Lv X, Wang X. Overexpression of IL-9 induced by STAT6 activation promotes the pathogenesis of chronic lymphocytic leukemia. Int J Clin Exp Pathol. 2014;7:2319–23.
pubmed: 24966942
pmcid: 4069881
Moga E, Cantó E, Vidal S, Juarez C, Sierra J, Briones J. Interleukin-15 enhances rituximab-dependent cytotoxicity against chronic lymphocytic leukemia cells and overcomes transforming growth factor beta-mediated immunosuppression. Exp Hematol. 2011;39:1064–71.
pubmed: 21864486
doi: 10.1016/j.exphem.2011.08.006
Pagano G, Botana IF, Wierz M, Roessner PM, Ioannou N, Zhou X, et al. Interleukin-27 potentiates CD8+ T-cell-mediated anti-tumor immunity in chronic lymphocytic leukemia. Haematologica. 2023;108:3011–24.
pubmed: 37345470
pmcid: 10620579
doi: 10.3324/haematol.2022.282474
Zhu F, McCaw L, Spaner DE, Gorczynski RM. Targeting the IL-17/IL-6 axis can alter growth of Chronic Lymphocytic Leukemia in vivo/in vitro. Leuk Res. 2018;66:28–38.
pubmed: 29353760
doi: 10.1016/j.leukres.2018.01.006
Huseni MA, Wang L, Klementowicz JE, Yuen K, Breart B, Orr C, et al. CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy. Cell Reports Med. 2022;4:100878.
doi: 10.1016/j.xcrm.2022.100878
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765–72.
pubmed: 8671665
doi: 10.1093/intimm/8.5.765
Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18:153–67.
pubmed: 28990585
doi: 10.1038/nri.2017.108
Jiménez-Fernández M, Rodríguez-Sinovas C, Cañes L, Ballester-Servera C, Vara A, Requena S, et al. CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes. Cell Mol Life Sci. 2022;79:468.
pubmed: 35930205
pmcid: 9355928
doi: 10.1007/s00018-022-04481-1
Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee CYQ, et al. T-cell exhaustion in chronic infections: Reversing the state of exhaustion and reinvigorating optimal protective immune responses. Front Immunol. 2018;9:2569.
pubmed: 30473697
pmcid: 6237934
doi: 10.3389/fimmu.2018.02569
Sun M, Gu P, Yang Y, Yu L, Jiang Z, Li J, et al. Mesoporous silica nanoparticles inflame tumors to overcome anti-PD-1 resistance through TLR4-NFκB axis. J Immunother Cancer. 2021;9:2508.
doi: 10.1136/jitc-2021-002508
Sun Z, Fourcade J, Pagliano O, Chauvin JM, Sander C, Kirkwood JM, et al. IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8+ T cells. Cancer Res. 2015;75:1635–44.
pubmed: 25720800
pmcid: 4401638
doi: 10.1158/0008-5472.CAN-14-3016
Park BV, Freeman ZT, Ghasemzadeh A, Chattergoon MA, Rutebemberwa A, Steigner J, et al. TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discov. 2016;6:1366–81.
pubmed: 27683557
pmcid: 5295786
doi: 10.1158/2159-8290.CD-15-1347
Rivas JR, Liu Y, Alhakeem SS, Eckenrode JM, Marti F, Collard JP, et al. Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia. Leukemia. 2021;35:3188–200.
pubmed: 33731852
pmcid: 8446094
doi: 10.1038/s41375-021-01217-1
Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017;129:3419–27.
pubmed: 28424162
pmcid: 5492091
doi: 10.1182/blood-2017-02-765685
Sordo‐bahamonde C, Lorenzo‐herrero S, González‐rodríguez AP, Payer ÁR, González‐garcía E, López‐soto A, et al. Lag‐3 blockade with relatlimab (Bms‐986016) restores anti‐leukemic responses in chronic lymphocytic leukemia. Cancers (Basel). 2021;13:2112.
pubmed: 33925565
doi: 10.3390/cancers13092112
Kosmaczewska A, Ciszak L, Suwalska K, Wolowiec D, Frydecka I. CTLA-4 overexpression in CD19+/CD5+ cells correlates with the level of cell cycle regulators and disease progression in B-CLL patients [8]. Leukemia. 2005;19:301–4.
pubmed: 15549146
doi: 10.1038/sj.leu.2403588
Gu D, Ao X, Yang Y, Chen Z, Xu X. Soluble immune checkpoints in cancer: Production, function and biological significance. J Immunother Cancer. 2018;6:1–14.
doi: 10.1186/s40425-018-0449-0
Capitani N, Patrussi L, Trentin L, Lucherini OM, Cannizzaro E, Migliaccio E, et al. S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis. Blood. 2012;120:4391–9.
pubmed: 23033271
doi: 10.1182/blood-2012-04-425959
Tatangelo V, Boncompagni G, Capitani N, Lopresti L, Manganaro N, Frezzato F, et al. p66Shc deficiency in chronic lymphocytic leukemia promotes chemokine receptor expression through the ROS-dependent inhibition of NF-κB. Front Oncol. 2022;12:877495.
pubmed: 35847884
pmcid: 9278989
doi: 10.3389/fonc.2022.877495
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Hallek 2008 Blood Glines for diagnois and treament of chrn lymph leuk. Blood. 2008;111:5446–56.
pubmed: 18216293
pmcid: 2972576
doi: 10.1182/blood-2007-06-093906
Visentin A, Bonaldi L, Rigolin GM, Mauro FR, Martines A, Frezzato F, et al. The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia. Br J Cancer. 2019;121:150–6.
pubmed: 31209327
pmcid: 6738078
doi: 10.1038/s41416-019-0502-x
Patrussi L, Capitani N, Cattaneo F, Manganaro N, Gamberucci A, Frezzato F, et al. p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from β-arrestin at early endosomes. Oncogene. 2018;37:1534–50.
pubmed: 29326436
doi: 10.1038/s41388-017-0066-2
Alcaraz-Serna A, Bustos-Morán E, Fernández-Delgado I, Calzada-Fraile D, Torralba D, Marina-Zárate E, et al. Immune synapse instructs epigenomic and transcriptomic functional reprogramming in dendritic cells. Sci Adv. 2021;7:eabb9965.
pubmed: 33536205
pmcid: 7857677
doi: 10.1126/sciadv.abb9965
Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, Carbone FR. T cell receptor antagonist peptides induce positive selection. Cell. 1994;76:17–27.
pubmed: 8287475
doi: 10.1016/0092-8674(94)90169-4
Cassioli C, Onnis A, Finetti F, Capitani N, Brunetti J, Compeer EB, et al. The Bardet–Biedl syndrome complex component BBS1 controls T cell polarity during immune synapse assembly. J Cell Sci. 2021;134:jcs258462.
pubmed: 34423835
doi: 10.1242/jcs.258462