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Cancer Immunology, Immunotherapy

, Volume 68, Issue 5, pp 861–870 | Cite as

Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy

  • Beatriz Sanchez-Correa
  • Nelson Lopez-Sejas
  • Esther Duran
  • Fernando Labella
  • Corona Alonso
  • Rafael SolanaEmail author
  • Raquel Tarazona
Focussed Research Review

Abstract

The incidence of some types of tumours has increased progressively in recent years and is expected to continue growing in the coming years due in part to the aging of the population. The design of new therapies based on natural killer (NK) cells opens new possibilities especially for the treatment of elderly patients who are particularly susceptible to the toxicity of conventional chemotherapy treatments. In recent years, the potential use of NK cells in cancer immunotherapy has been of great interest thanks to advances in the study of NK cell biology. The identification of key points (checkpoints) in the activation of NK cells that can be regulated by monoclonal antibodies has allowed the design of new therapeutic strategies based on NK cells. However, there are still limitations for its use and the first clinical trials blocking KIR inhibitory receptors have shown little efficacy by inhibiting the maturation of NK cells. Blockade of other inhibitory receptors such as TIGIT, TIM3, LAG3 and PD1 may represent novel strategies to increase NK function in cancer patients. Altogether, the identification of NK cell and tumour cell markers of resistance or susceptibility to the action of NK cells will contribute to identifying those patients that will most likely benefit from NK cell-based immunotherapy.

Keywords

NK cells miRNA Immunotherapy Checkpoint blockade PIVAC 17 

Abbreviations

AML

Acute myeloid leukaemia

CAR

Chimeric antigen receptor

CTL

Cytotoxic T lymphocytes

HLA

Human leukocyte antigen

IFN

Interferon

IL

Interleukin

KIR

Killer cell immunoglobulin-like receptors

LAG-3

Lymphocyte activating gene 3

MHC

Major histocompatibility complex

miRNAs

MicroRNAs

mAb

Monoclonal antibody

NCRs

Natural cytotoxicity receptors

NK

Natural killer

NSCLC

Non-small cell lung cancer

PD-1

Programmed death-1

TIM-3

T cell immunoglobulin and mucin domain 3

TIGIT

T cell immunoreceptor with Ig and ITIM domains

Notes

Author contributions

BS-C, RS and RT designed and wrote the first draft of the manuscript. NL-S, ED, FL and CA discussed the manuscript sections and contributed with updated references. All authors revised and agreed the final version of the paper.

Funding

This work was supported by Grants PI13/02691 (to Rafael Solana), PI16/01615 (to Rafael Solana and Corona Alonso) by Instituto de Salud Carlos III, SAF2013-46161-R and SAF2017-87538-R (to Raquel Tarazona) from the Agencia Estatal de Investigacion (Ministry of Economy and Competitiveness of Spain), IB16164 and Grants to INPATT (CTS040) research group (GR18085) from Consejeria de Economia e Infraestructura (Junta de Extremadura) (to Raquel Tarazona), cofinanced by European Regional Development Funds (FEDER) “Una manera de hacer Europa”.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Lorenzo-Herrero S, Lopez-Soto A, Sordo-Bahamonde C, Gonzalez-Rodriguez AP, Vitale M, Gonzalez S (2019) NK cell-based immunotherapy in cancer metastasis. Cancers 11:29CrossRefGoogle Scholar
  2. 2.
    Rady M, Abou-Aisha K (2018) The antitumor immunity mediated by NK cells: the role of the NCRs. Open Cancer Immunol J 07:7–15CrossRefGoogle Scholar
  3. 3.
    Bottcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, Rogers NC, Sahai E, Zelenay S, Reis e Sousa C (2018) NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172:1022–1037CrossRefGoogle Scholar
  4. 4.
    Fessenden TB, Duong E, Spranger S (2018) A team effort: natural killer cells on the first leg of the tumor immunity relay race. J Immunother Cancer 6:67CrossRefGoogle Scholar
  5. 5.
    Davis ZB, Vallera DA, Miller JS, Felices M (2017) Natural killer cells unleashed: checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. Semin Immunol 31:64–75CrossRefGoogle Scholar
  6. 6.
    Montaldo E, Zotto GD, Chiesa MD, Mingari MC, Moretta A, Maria AD, Moretta L (2013) Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function. Cytometry A 83:702–713CrossRefGoogle Scholar
  7. 7.
    Bezman NA, Kim CC, Sun JC, Min-Oo G, Hendricks DW, Kamimura Y, Best JA, Goldrath AW, Lanier LL (2012) Molecular definition of the identity and activation of natural killer cells. Nat Immunol 13:1000–1009CrossRefGoogle Scholar
  8. 8.
    Vivier E, Ugolini S (2011) Natural killer cells: from basic research to treatments. Front Immunol 2:18CrossRefGoogle Scholar
  9. 9.
    Casado JG, Pawelec G, Morgado S, Sanchez-Correa B, Delgado E, Gayoso I, Duran E, Solana R, Tarazona R (2009) Expression of adhesion molecules and ligands for activating and costimulatory receptors involved in cell-mediated cytotoxicity in a large panel of human melanoma cell lines. Cancer Immunol Immunother 58:1517–1526CrossRefGoogle Scholar
  10. 10.
    Sanchez-Correa B, Morgado S, Gayoso I, Bergua JM, Casado JG, Arcos MJ, Bengochea ML, Duran E, Solana R, Tarazona R (2011) Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands. Cancer Immunol Immunother 60:1195–1205CrossRefGoogle Scholar
  11. 11.
    Lam RA, Chwee JY, Le BN, Sauer M, von Pogge SE, Gasser S (2013) Regulation of self-ligands for activating natural killer cell receptors. Ann Med 45:384–394CrossRefGoogle Scholar
  12. 12.
    Morgado S, Sanchez-Correa B, Casado JG, Duran E, Gayoso I, Labella F, Solana R, Tarazona R (2011) NK cell recognition and killing of melanoma cells is controlled by multiple activating receptor-ligand interactions. J Innate Immun 3:365–373CrossRefGoogle Scholar
  13. 13.
    Sanchez-Correa B, Gayoso I, Bergua JM, Casado JG, Morgado S, Solana R, Tarazona R (2012) Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol Cell Biol 90:109–115CrossRefGoogle Scholar
  14. 14.
    Sanchez-Correa B, Bergua JM, Campos C, Gayoso I, Arcos MJ, Banas H, Morgado S, Casado JG, Solana R, Tarazona R (2013) Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine 61:885–891CrossRefGoogle Scholar
  15. 15.
    Balsamo M, Vermi W, Parodi M, Pietra G, Manzini C, Queirolo P, Lonardi S, Augugliaro R, Moretta A, Facchetti F, Moretta L, Mingari MC, Vitale M (2012) Melanoma cells become resistant to NK-cell-mediated killing when exposed to NK-cell numbers compatible with NK-cell infiltration in the tumor. Eur J Immunol 42:1833–1842CrossRefGoogle Scholar
  16. 16.
    Carlsten M, Norell H, Bryceson YT, Poschke I, Schedvins K, Ljunggren HG, Kiessling R, Malmberg KJ (2009) Primary human tumor cells expressing CD155 impair tumor targeting by down-regulating DNAM-1 on NK cells. J Immunol 183:4921–4930CrossRefGoogle Scholar
  17. 17.
    Sanchez-Correa B, Bergua JM, Pera A, Campos C, Arcos MJ, Banas H, Duran E, Solana R, Tarazona R (2017) in vitro culture with interleukin-15 leads to expression of activating receptors and recovery of natural killer cell function in acute myeloid leukemia patients. Front Immunol 8:931CrossRefGoogle Scholar
  18. 18.
    Krieg S, Ullrich E (2012) Novel immune modulators used in hematology: impact on NK cells. Front Immunol 3:388Google Scholar
  19. 19.
    Terme M, Ullrich E, Delahaye NF, Chaput N, Zitvogel L (2008) Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nat Immunol 9:486–494CrossRefGoogle Scholar
  20. 20.
    Kim N, Kim HS (2018) Targeting checkpoint receptors and molecules for therapeutic modulation of natural killer cells. Front Immunol 9:2041CrossRefGoogle Scholar
  21. 21.
    Kwon HJ, Kim N, Kim HS (2017) Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy. Exp Mol Med 49:e311CrossRefGoogle Scholar
  22. 22.
    Chiossone L, Vienne M, Kerdiles YM, Vivier E (2017) Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more. Semin Immunol 31:55–63CrossRefGoogle Scholar
  23. 23.
    Tarazona R, Duran E, Solana R (2016) Natural killer cell recognition of melanoma: new clues for a more effective immunotherapy. Front Immunol 6:649CrossRefGoogle Scholar
  24. 24.
    Burugu S, Dancsok AR, Nielsen TO (2018) Emerging targets in cancer immunotherapy. Semin Cancer Biol 52:39–52CrossRefGoogle Scholar
  25. 25.
    Li Y, Hermanson DL, Moriarity BS, Kaufman DS (2018) Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23:181–192CrossRefGoogle Scholar
  26. 26.
    Vey N, Goncalves A, Karlin L, Lebouvier-Sadot S, Broussais F, Marie D, Berton-Rigaud D, Andre P, Zerbib RA, Buffet R, Prébet T, Charbonnier A, Rey J, Pigneux A, Bennouna J, Boissel N, Salles GA (2015) A phase 1 dose-escalation study of IPH2102 (lirilumab, BMS-986015, LIRI), a fully human anti KIR monoclonal antibody (mAb) in patients (pts) with various hematologic (HEM) or solid malignancies (SOL). J Clin Immunol (suppl):Abstract 3065–2015 ASCO Annual MeetingGoogle Scholar
  27. 27.
    Corsello SM, Barnabei A, Marchetti P, De VL, Salvatori R, Torino F (2013) Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 98:1361–1375CrossRefGoogle Scholar
  28. 28.
    Torino F, Corsello SM, Salvatori R (2016) Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol 28:278–287CrossRefGoogle Scholar
  29. 29.
    Kasenda B, Kuhnl A, Chau I (2016) Beginning of a novel frontier: T-cell-directed immune manipulation in lymphomas. Expert Rev Hematol 9:123–135CrossRefGoogle Scholar
  30. 30.
    Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ (2016) Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 3:16011CrossRefGoogle Scholar
  31. 31.
    Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097–2100CrossRefGoogle Scholar
  32. 32.
    Velardi A, Ruggeri L, Mancusi A, Aversa F, Christiansen FT (2009) Natural killer cell allorecognition of missing self in allogeneic hematopoietic transplantation: a tool for immunotherapy of leukemia. Curr Opin Immunol 21:525–530CrossRefGoogle Scholar
  33. 33.
    Vey N, Bourhis JH, Boissel N, Bordessoule D, Prebet T, Charbonnier A, Etienne A, Andre P, Romagne F, Benson D, Dombret H, Olive D (2012) A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood 120:4317–4323CrossRefGoogle Scholar
  34. 34.
    Raulet DH, Vance RE (2006) Self-tolerance of natural killer cells. Nat Rev Immunol 6:520–531CrossRefGoogle Scholar
  35. 35.
    Jaeger BN, Vivier E (2012) When NK cells overcome their lack of education. J Clin Invest 122:3053–3056CrossRefGoogle Scholar
  36. 36.
    Shen X, Zhao B (2018) Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ 362:k3529CrossRefGoogle Scholar
  37. 37.
    Oyer JL, Gitto SB, Altomare DA, Copik AJ (2018) PD-L1 blockade enhances anti-tumor efficacy of NK cells. Oncoimmunology 7:e1509819CrossRefGoogle Scholar
  38. 38.
    Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA (2010) The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116:2286–2294CrossRefGoogle Scholar
  39. 39.
    Wiesmayr S, Webber SA, Macedo C, Popescu I, Smith L, Luce J, Metes D (2012) Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. Eur J Immunol 42:541–550CrossRefGoogle Scholar
  40. 40.
    Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, Moretta L, Moretta A, Marcenaro E (2017) Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol 139:335–346CrossRefGoogle Scholar
  41. 41.
    Solomon BL, Garrido-Laguna I (2018) TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother 67:1659–1667CrossRefGoogle Scholar
  42. 42.
    Tarazona R, Sanchez-Correa B, Casas-Aviles I, Campos C, Pera A, Morgado S, Lopez-Sejas N, Hassouneh F, Bergua JM, Arcos MJ, Banas H, Casado JG, Duran E, Labella F, Solana R (2017) Immunosenescence: limitations of natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother 66:233–245CrossRefGoogle Scholar
  43. 43.
    Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14:561–584CrossRefGoogle Scholar
  44. 44.
    Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, Wang Z, Wu Q, Peng H, Wei H, Sun R, Tian Z (2018) Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol 19:723–732CrossRefGoogle Scholar
  45. 45.
    Blake SJ, Stannard K, Liu J, Allen S, Yong MC, Mittal D, Aguilera AR, Miles JJ, Lutzky VP, de Andrade LF, Martinet L, Colonna M, Takeda K, Kuhnel F, Gurlevik E, Bernhardt G, Teng MW, Smyth MJ (2016) Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discov 6:446–459CrossRefGoogle Scholar
  46. 46.
    Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44:989–1004CrossRefGoogle Scholar
  47. 47.
    Klingemann H, Boissel L, Toneguzzo F (2016) Natural killer cells for immunotherapy—advantages of the NK-92 cell line over blood NK cells. Front Immunol 7:91CrossRefGoogle Scholar
  48. 48.
    Dragomir M, Chen B, Fu X, Calin GA (2018) Key questions about the checkpoint blockade-are microRNAs an answer? Cancer Biol Med 15:103–115CrossRefGoogle Scholar
  49. 49.
    Romano G, Kwong LN (2018) Diagnostic and therapeutic applications of miRNA-based strategies to cancer immunotherapy. Cancer Metastasis Rev 37:45–53CrossRefGoogle Scholar
  50. 50.
    Yang J, Liu R, Deng Y, Qian J, Lu Z, Wang Y, Zhang D, Luo F, Chu Y (2017) MiR-15a/16 deficiency enhances anti-tumor immunity of glioma-infiltrating CD8 + T cells through targeting mTOR. Int J Cancer 141:2082–2092CrossRefGoogle Scholar
  51. 51.
    Wei J, Nduom EK, Kong LY, Hashimoto Y, Xu S, Gabrusiewicz K, Ling X, Huang N, Qiao W, Zhou S, Ivan C, Fuller GN, Gilbert MR, Overwijk W, Calin GA, Heimberger AB (2016) MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. Neuro Oncol 18:639–648CrossRefGoogle Scholar
  52. 52.
    Huber V, Vallacchi V, Fleming V, Hu X, Cova A, Dugo M, Shahaj E, Sulsenti R, Vergani E, Filipazzi P, De Laurentiis A, Lalli L, Di GL, Patuzzo R, Vergani B, Casiraghi E, Cossa M, Gualeni A, Bollati V, Arienti F, De BF, Mariani L, Villa A, Altevogt P, Umansky V, Rodolfo M, Rivoltini L (2018) Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma. J Clin Invest 128:5505–5516CrossRefGoogle Scholar
  53. 53.
    Li Q, Johnston N, Zheng X, Wang H, Zhang X, Gao D, Min W (2016) miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion. Oncotarget 7:53735–53750Google Scholar
  54. 54.
    Sanchez-Correa B, Campos C, Pera A, Bergua JM, Arcos MJ, Banas H, Casado JG, Morgado S, Duran E, Solana R, Tarazona R (2016) Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies? Cancer Immunol Immunother 65:453–463CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Immunology UnitUniversity of ExtremaduraCaceresSpain
  2. 2.Histology and Pathology Unit, Faculty of VeterinaryUniversity of ExtremaduraCaceresSpain
  3. 3.Immunology UnitUniversidad de CordobaCordobaSpain
  4. 4.Instituto Maimónides de Investigación Biomédica (IMIBIC)CórdobaSpain
  5. 5.Reina Sofia University HospitalCórdobaSpain

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