Accumulating evidence indicates that immune checkpoint inhibitors (ICIs) can restore CD8+ cytotoxic T lymphocyte (CTL) functions in preclinical models of acute myeloid leukemia (AML). However, ICIs targeting programmed cell death 1 (PDCD1, best known as PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have limited clinical efficacy in patients with AML. Natural killer (NK) cells are central players in AML-targeting immune responses. However, little is known on the relationship between co-inhibitory receptors expressed by NK cells and the ability of the latter to control AML. Here, we show that hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) is highly expressed by NK cells from AML patients, correlating with improved functional licensing and superior effector functions. Altogether, our data indicate that NK cell frequency as well as TIM-3 expression levels constitute prognostically relevant biomarkers of active immunity against AML.

Biomedical Center Faculty of Medicine in Pilsen Charles University Czech Republic

Caryl and Israel Englander Institute for Precision Medicine New York NY USA

Department of Dermatology Yale University School of Medicine New Haven CT USA

Department of Hematology and Oncology University Hospital in Pilsen Czech Republic

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Medicine University of Chicago Chicago IL USA

Department of Radiation Oncology Weill Cornell Medical College New York NY USA

Institute of Clinical and Experimental Hematology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Hematology and Blood Transfusion Prague Czech Republic

Laboratory of Tumor Immunology Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Sandra and Edward Meyer Cancer Center New York NY USA

Sotio Prague Czech Republic

Université de Paris Paris France

Zobrazit více v PubMed

Huntington ND, Cursons J, Rautela J.. The cancer-natural killer cell immunity cycle. Nat Rev Cancer. 2020;20(8):437–12. doi:10.1038/s41568-020-0272-z. PubMed DOI

Buque A, Bloy N, Perez-Lanzon M, Iribarren K, Humeau J, Pol JG, et al. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat Commun. 2020;11(1):3819. doi:10.1038/s41467-020-17644-0. PubMed DOI PMC

Cerwenka A, Lanier LL. Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol. 2016;16(2):112–123. doi:10.1038/nri.2015.9. PubMed DOI

Lopez-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. Control of Metastasis by NK Cells. Cancer Cell. 2017;32(2):135–154. doi:10.1016/j.ccell.2017.06.009. PubMed DOI

Zhang H, Vijayan D, Li XY, Robson SC, Geetha N, Teng MWL, et al. The role of NK cells and CD39 in the immunological control of tumor metastases. Oncoimmunology. 2019;8(6):e1593809. doi:10.1080/2162402X.2019.1593809. PubMed DOI PMC

Minute L, Teijeira A, Sanchez-Paulete AR, Ochoa MC, Alvarez M, Otano I, et al. Cellular cytotoxicity is a form of immunogenic cell death. J Immunother Cancer. 2020;8:1. doi:10.1136/jitc-2019-000325. PubMed DOI PMC

Bottcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell. 2018;172(5):1022–1037 e1014. doi:10.1016/j.cell.2018.01.004. PubMed DOI PMC

Rao S, Gharib K, Han A. Cancer Immunosurveillance by T Cells. Int Rev Cell Mol Biol. 2019;342:149–173. PubMed

Galluzzi L, Chan TA, Kroemer G, Wolchok JD, Lopez-Soto A. The hallmarks of successful anticancer immunotherapy. Sci Transl Med. 2018;10:459. doi:10.1126/scitranslmed.aat7807. PubMed DOI

Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol. 2013;31:227–258. doi:10.1146/annurev-immunol-020711-075005. PubMed DOI PMC

Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol. 2015;15(4):243–254. doi:10.1038/nri3799. PubMed DOI

Russick J, Torset C, Hemery E, Cremer I. NK cells in the tumor microenvironment: prognostic and theranostic impact. Recent advances and trends. Semin Immunol. 2020;5:101407. doi:10.1016/j.smim.2020.101407. PubMed DOI

Carlsten M, Jaras M. Natural killer cells in myeloid malignancies: immune surveillance, NK cell dysfunction, and pharmacological opportunities to bolster the endogenous NK cells. Front Immunol. 2019;10:2357. doi:10.3389/fimmu.2019.02357. PubMed DOI PMC

Truxova I, Kasikova L, Salek C, Hensler M, Lysak D, Holicek P, et al. Calreticulin exposure on malignant blasts correlates with improved natural killer cell-mediated cytotoxicity in acute myeloid leukemia patients. Haematologica. 2020;105(7):1868–1878. doi:10.3324/haematol.2019.223933. PubMed DOI PMC

Estey EH. Acute myeloid leukemia: 2021 update on risk-stratification and management. Am J Hematol. 2020;95(11):1368–1398. doi:10.1002/ajh.25975. PubMed DOI

Petroni G, Buque A, Zitvogel L, Kroemer G, Galluzzi L. Immunomodulation by targeted anticancer agents. Cancer Cell. 2020 Dec 17;S1535-6108(20)30601-2. PubMed

Sprooten J, Agostinis P, Garg AD. Type I interferons and dendritic cells in cancer immunotherapy. Int Rev Cell Mol Biol. 2019;348:217–262. PubMed

Cruijsen M, Lubbert M, Wijermans P, Huls G. Clinical results of hypomethylating agents in AML treatment. J Clin Med. 2014;4(1):1–17. doi:10.3390/jcm4010001. PubMed DOI PMC

Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE, et al. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, Phase II study. Cancer Discov. 2019;9(3):370–383. doi:10.1158/2159-8290.CD-18-0774. PubMed DOI PMC

Stahl M, Goldberg AD. Immune checkpoint inhibitors in acute myeloid leukemia: novel combinations and therapeutic targets. Curr Oncol Rep. 2019;21(4):37. doi:10.1007/s11912-019-0781-7. PubMed DOI

Galluzzi L, Humeau J, Buque A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020Dec;17(12):725-741. PubMed

Iams WT, Porter J, Horn L. Immunotherapeutic approaches for small-cell lung cancer. Nat Rev Clin Oncol. 2020;17(5):300–312. doi:10.1038/s41571-019-0316-z. PubMed DOI PMC

Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017;14(8):463–482. doi:10.1038/nrclinonc.2017.43. PubMed DOI

Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol. 2015;33(17):1974–1982. doi:10.1200/JCO.2014.59.4358. PubMed DOI PMC

Krupka C, Kufer P, Kischel R, Zugmaier G, Lichtenegger FS, Kohnke T, et al. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. Leukemia. 2016;30(2):484–491. doi:10.1038/leu.2015.214. PubMed DOI

Zhang L, Gajewski TF, Kline JPD. 1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114(8):1545–1552. doi:10.1182/blood-2009-03-206672. PubMed DOI PMC

Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, et al. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood. 2010;116(14):2484–2493. doi:10.1038/nri3405. PubMed DOI PMC

Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117(17):4501–4510. doi:10.1182/blood-2010-10-310425. PubMed DOI PMC

Fucikova J, Rakova J, Hensler M, Kasikova L, Belicova L, Hladikova K, et al. TIM-3 dictates functional orientation of the immune infiltrate in ovarian cancer. Clin Cancer Res. 2019;25(15):4820–4831. doi:10.1158/1078-0432.CCR-18-4175. PubMed DOI

Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32(18):2847–2849. doi:10.1093/bioinformatics/btw313. PubMed DOI

Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–287. doi:10.1089/omi.2011.0118. PubMed DOI PMC

Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–510. doi:10.1038/ni1582. PubMed DOI

Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–242. PubMed PMC

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. doi:10.1038/nrc3239. PubMed DOI PMC

Han X, Vesely MD. Stimulating T cells against cancer with agonist immunostimulatory monoclonal antibodies. Int Rev Cell Mol Biol. 2019;342:1–25. PubMed PMC

Fucikova J, Kline JP, Galluzzi L, Spisek R. Calreticulin arms NK cells against leukemia. Oncoimmunology. 2020;9(1):1671763. doi:10.1080/2162402X.2019.1671763. PubMed DOI PMC

Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN, et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest. 2018;128(10):4654–4668. doi:10.1172/JCI99317. PubMed DOI PMC

Da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, et al. Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res. 2014;2(5):410–422. doi:10.1158/2326-6066.CIR-13-0171. PubMed DOI PMC

Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19(7):723–732. doi:10.1038/s41590-018-0132-0. PubMed DOI

Maas RJ, Hoogstad-van Evert JS, Van Der Meer JM, Mekers V, Rezaeifard S, Korman AJ, et al. TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer. Oncoimmunology. 2020;9(1):1843247. doi:10.1080/2162402X.2020.1843247. PubMed DOI PMC

Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020;8:1. doi:10.1136/jitc-2020-000911. PubMed DOI PMC

Gleason MK, Lenvik TR, McCullar V, Felices M, O’Brien MS, Cooley SA, et al. Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9. Blood. 2012;119(13):3064–3072. doi:10.1182/blood-2011-06-360321. PubMed DOI PMC

Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020;20(3):173–185. doi:10.1038/s41577-019-0224-6. PubMed DOI PMC

Nagahara K, Arikawa T, Oomizu S, Kontani K, Nobumoto A, Tateno H, et al. Galectin-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions. J Immunol. 2008;181(11):7660–7669. doi:10.4049/jimmunol.181.11.7660. PubMed DOI PMC

Martinek J, Wu TC, Cadena D, Banchereau J, Palucka K. Interplay between dendritic cells and cancer cells. Int Rev Cell Mol Biol. 2019;348:179–215. PubMed

Balan S, Saxena M, Bhardwaj N. Dendritic cell subsets and locations. Int Rev Cell Mol Biol. 2019;348:1–68. PubMed

Ndhlovu LC, Lopez-Verges S, Barbour JD, Jones RB, Jha AR, Long BR, et al. Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood. 2012;119(16):3734–3743. doi:10.1182/blood-2011-11-392951. PubMed DOI PMC

Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, et al. Anti-NKG2A mAb Is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell. 2018;175(7):1731–1743 e1713. doi:10.1016/j.cell.2018.10.014. PubMed DOI PMC

Nguyen R, Wu H, Pounds S, Inaba H, Ribeiro RC, Cullins D, et al. A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia. J Immunother Cancer. 2019;7(1):81. doi:10.1186/s40425-019-0564-6. PubMed DOI PMC

NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia