LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8⁺ T cells for improving anti-PD-1 antibody therapy

References

• Ganesan AP, Clarke J, Wood O, Garrido-Martin EM, Chee SJ, Mellows T, Samaniego-Castruita D, Singh D, Seumois G, Alzetani A, et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol. 2017;18(8):940–14. doi:10.1038/ni.3775.
   PubMed Web of Science ®Google Scholar
• Luoma AM, Suo S, Williams HL, Sharova T, Sullivan K, Manos M, Bowling P, Hodi FS, Rahma O, Sullivan RJ, et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell. 2020;182(3):655–671 e622. doi:10.1016/j.cell.2020.06.001.
   PubMed Web of Science ®Google Scholar
• Song Y, Zhang B, Xin D, Kou X, Tan Z, Zhang S, Sun M, Zhou J, Fan M, Zhang M, et al. First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. Nat Med. 2023;29(2):473–482. doi:10.1038/s41591-022-02179-2.
   PubMed Web of Science ®Google Scholar
• Yan Q, Zhao Y, Ma R, Wang B, Zhu Z, Li T, He D, Hocart CH, Zhou Y. Capping the hydroxyl groups (-OH) of alpha-cellulose to reduce hy-groscopicity for accurate (18)O/(16)O measurement by EA/Py/IRMS. Talanta. 2023;262:124698. doi:10.1016/j.talanta.2023.124698.
   PubMed Web of Science ®Google Scholar
• Li H, van der Leun AM, Yofe I, Lubling Y, Gelbard-Solodkin D, van Akkooi ACJ, van den Braber M, Rozeman EA, Haanen J, Blank CU, et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell. 2019;176(4):775–789 e718. doi:10.1016/j.cell.2018.11.043.
   PubMed Web of Science ®Google Scholar
• 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 e828. doi:10.1016/j.immuni.2020.04.014.
   PubMed Web of Science ®Google Scholar
• Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Sci. 2016;354(6316):1160–1165. doi:10.1126/science.aaf2807.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Zehn D, Thimme R, Lugli E, de Almeida GP, Oxenius A. ‘Stem-like’ precursors are the fount to sustain persistent CD8+ T cell responses. Nat Immunol. 2022;23(6):836–847. doi:10.1038/s41590-022-01219-w.
   PubMed Web of Science ®Google Scholar
• Yang M, Lu J, Zhang G, Wang Y, He M, Xu Q, Xu C, Liu H. CXCL13 shapes immunoactive tumor microenvironment and enhances the efficacy of PD-1 checkpoint blockade in high-grade serous ovarian cancer. J Immunother Cancer. 2021;9(1):e001136. doi:10.1136/jitc-2020-001136.
   PubMed Web of Science ®Google Scholar
• Smith KA. Interleukin-2: inception, impact, and implications. Sci. 1988;240(4856):1169–1176. doi:10.1126/science.3131876.
   PubMed Web of Science ®Google Scholar
• Lutz V, Hellmund VM, Picard FSR, Raifer H, Ruckenbrod T, Klein M, Bopp T, Savai R, Duewell P, Keber CU, et al. IL18 receptor signaling regulates tumor-reactive CD8+ T-cell exhaustion via activation of the IL2/STAT5/mTOR Pathway in a pancreatic cancer model. Cancer Immunol Res. 2023;11(4):421–434. doi:10.1158/2326-6066.CIR-22-0398.
   PubMed Web of Science ®Google Scholar
• Gaggero S, Martinez-Fabregas J, Cozzani A, Fyfe PK, Leprohon M, Yang J, Thomasen FE, Winkelmann H, Magnez R, Conti AG, et al. IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein. Sci Immunol. 2022;7(78):eade5686. doi:10.1126/sciimmunol.ade5686.
   PubMed Web of Science ®Google Scholar
• Li P, Mitra S, Spolski R, Oh J, Liao W, Tang Z, Mo F, Li X, West EE, Gromer D, et al. STAT5-mediated chromatin interactions in superenhancers activate IL-2 highly inducible genes: functional dissection of the Il2ra gene locus. Proc Natl Acad Sci U S A. 2017;114(46):12111–12119. doi:10.1073/pnas.1714019114.
   PubMed Web of Science ®Google Scholar
• Kradin RL, Kurnick JT, Lazarus DS, Preffer FI, Dubinett SM, Pinto CE, Gifford J, Davidson E, Grove B, Callahan RJ, et al. Tumour-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer. Lancet. 1989;1(8638):577–580. doi:10.1016/S0140-6736(89)91609-7.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–5458. doi:10.4049/jimmunol.1490019.
   PubMed Web of Science ®Google Scholar
• Hons M, Kopf A, Hauschild R, Leithner A, Gaertner F, Abe J, Renkawitz J, Stein JV, Sixt M. Chemokines and integrins independently tune actin flow and substrate friction during intranodal migration of T cells. Nat Immunol. 2018;19(6):606–616. doi:10.1038/s41590-018-0109-z.
   PubMed Web of Science ®Google Scholar
• Stinchcombe JC, Asano Y, Kaufman CJG, Bohlig K, Peddie CJ, Collinson LM, Nadler A, Griffiths GM. Ectocytosis renders T cell receptor signaling self-limiting at the immune synapse. Sci. 2023;380(6647):818–823. doi:10.1126/science.abp8933.
   PubMed Web of Science ®Google Scholar
• Samstag Y, Eibert SM, Klemke M, Wabnitz GH. Actin cytoskeletal dynamics in T lymphocyte activation and migration. J Leukoc Biol. 2003;73(1):30–48. doi:10.1189/jlb.0602272.
   PubMed Web of Science ®Google Scholar
• Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol. 2005;5(7):546–559. doi:10.1038/nri1646.
   PubMed Web of Science ®Google Scholar
• Yuan Y, Adam A, Zhao C, Chen H. Recent advancements in the mechanisms underlying resistance to PD-1/PD-L1 blockade immunotherapy. Cancers Basel. 2021;13(4):663. doi:10.3390/cancers13040663.
   PubMed Web of Science ®Google Scholar
• Wang S, Hao J, Wang H, Fang Y, Tan L. Efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer. Oncoimmunology. 2018;7(8):e1457600. doi:10.1080/2162402X.2018.1457600.
   PubMed Web of Science ®Google Scholar
• De Biasi S, Gibellini L, Lo Tartaro D, Puccio S, Rabacchi C, Mazza EMC, Brummelman J, Williams B, Kaihara K, Forcato M, et al. Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy. Nat Commun. 2021;12(1):1669. doi:10.1038/s41467-021-21928-4.
   PubMed Web of Science ®Google Scholar
• Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M, Dimeloe S, Kiialainen A, Hanhart J, Schill C, Hess C, et al. A transcriptionally and functionally distinct PD-1(+) CD8(+) T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med. 2018;24(7):994–1004. doi:10.1038/s41591-018-0057-z.
   PubMed Web of Science ®Google Scholar
• Gerard A, Cope AP, Kemper C, Alon R, Kochl R. LFA-1 in T cell priming, differentiation, and effector functions. Trends Immunol. 2021;42(8):706–722. doi:10.1016/j.it.2021.06.004.
   PubMed Web of Science ®Google Scholar
• Lotscher J, Marti ILAA, Kirchhammer N, Cribioli E, Giordano Attianese GMP, Trefny MP, Lenz M, Rothschild SI, Strati P, Kunzli M, et al. Magnesium sensing via LFA-1 regulates CD8+ T cell effector function. Cell. 2022;185(4):585–602 e529. doi:10.1016/j.cell.2021.12.039.
   PubMed Web of Science ®Google Scholar
• Hickman A, Koetsier J, Kurtanich T, Nielsen MC, Winn G, Wang Y, Bentebibel SE, Shi L, Punt S, Williams L, et al. LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade. J Clin Invest. 2022;132(13). doi:10.1172/JCI154152.
   PubMed Web of Science ®Google Scholar
• Perro M, Iannacone M, von Andrian UH, Peixoto A. Role of LFA-1 integrin in the control of a lymphocytic choriomeningitis virus (LCMV) infection. Virulence. 2020;11(1):1640–1655. doi:10.1080/21505594.2020.1845506.
   PubMed Web of Science ®Google Scholar
• Hosseini BH, Louban I, Djandji D, Wabnitz GH, Deeg J, Bulbuc N, Samstag Y, Gunzer M, Spatz JP, Hammerling GJ. Immune synapse formation determines interaction forces between T cells and antigen-presenting cells measured by atomic force microscopy. Proc Natl Acad Sci U S A. 2009;106(42):17852–17857. doi:10.1073/pnas.0905384106.
   PubMed Web of Science ®Google Scholar
• Oh SC, Kim SE, Jang IH, Kim SM, Lee SY, Lee S, Chu IS, Yoon SR, Jung H, Choi I, et al. NgR1 is an NK cell inhibitory receptor that destabilizes the immunological synapse. Nat Immunol. 2023;24(3):463–473. doi:10.1038/s41590-022-01394-w.
   PubMed Web of Science ®Google Scholar
• Rosenthal LA, Winestock KD, Finbloom DS. IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts. Cell Immunol. 1997;181(2):172–181. doi:10.1006/cimm.1997.1208.
   PubMed Web of Science ®Google Scholar
• Liu Y, Yang T, Li H, Li MH, Liu J, Wang YT, Yang SX, Zheng J, Luo XY, Lai Y, et al. BD750, a benzothiazole derivative, inhibits T cell proliferation by affecting the JAK3/STAT5 signalling pathway. Br J Pharmacol. 2013;168(3):632–643. doi:10.1111/j.1476-5381.2012.02172.x.
   PubMed Web of Science ®Google Scholar
• Smith A, Stanley P, Jones K, Svensson L, McDowall A, Hogg N. The role of the integrin LFA-1 in T-lymphocyte migration. Immunol Rev. 2007;218(1):135–146. doi:10.1111/j.1600-065X.2007.00537.x.
   PubMedGoogle Scholar
• Wang MS, Hu Y, Sanchez EE, Xie X, Roy NH, de Jesus M, Winer BY, Zale EA, Jin W, Sachar C, et al. Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity. Nat Commun. 2022;13(1):3222. doi:10.1038/s41467-022-30809-3.
   PubMed Web of Science ®Google Scholar
• Xiong X, Chen S, Shen J, You H, Yang H, Yan C, Fang Z, Zhang J, Cai X, Dong X, et al. Cannabis suppresses antitumor immunity by inhibiting JAK/STAT signaling in T cells through CNR2. Sig Transduct Target Ther. 2022;7(1):99. doi:10.1038/s41392-022-00918-y.
   PubMed Web of Science ®Google Scholar
• Dai Z, Sezin T, Chang Y, Lee EY, Wang EHC, Christiano AM. Induction of T cell exhaustion by JAK1/3 inhibition in the treatment of alopecia areata. Front Immunol. 2022;13:955038. doi:10.3389/fimmu.2022.955038.
   PubMed Web of Science ®Google Scholar
• Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Sig Transduct Target Ther. 2021;6(1):402. doi:10.1038/s41392-021-00791-1.
   PubMed Web of Science ®Google Scholar
• Ross SH, Cantrell DA. Signaling and function of interleukin-2 in T lymphocytes. Annu Rev Immunol. 2018;36(1):411–433. doi:10.1146/annurev-immunol-042617-053352.
   PubMed Web of Science ®Google Scholar
• Bae J, Liu L, Moore C, Hsu E, Zhang A, Ren Z, Sun Z, Wang X, Zhu J, Shen J, et al. IL-2 delivery by engineered mesenchymal stem cells re-invigorates CD8(+) T cells to overcome immunotherapy resistance in cancer. Nat Cell Biol. 2022;24(12):1754–1765. doi:10.1038/s41556-022-01024-5.
   PubMedGoogle Scholar
• Tichet M, Wullschleger S, Chryplewicz A, Fournier N, Marcone R, Kauzlaric A, Homicsko K, Deak LC, Umana P, Klein C, et al. Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8(+) T cells and reprogramming macrophages. Immunity. 2023;56(1):162–179 e166. doi:10.1016/j.immuni.2022.12.006.
   PubMed Web of Science ®Google Scholar
• Liu Y, Zhou N, Zhou L, Wang J, Zhou Y, Zhang T, Fang Y, Deng J, Gao Y, Liang X, et al. IL-2 regulates tumor-reactive CD8(+) T cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol. 2021;22(3):358–369. doi:10.1038/s41590-020-00850-9.
   PubMed Web of Science ®Google Scholar