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Roles of NKT cells in cancer immunotherapy

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Abstract

Cancer immunotherapy has emerged as an effective therapeutic strategy to treat cancer. Among diverse immune populations, invariant natural killer T (iNKT) cells have shown potent antitumor activity by linking innate and adaptive immune systems. Upon activation by lipid antigens on CD1d molecules, iNKT cells rapidly produce various cytokines and trigger antitumor immunity directly or indirectly by activating other antitumor immune cells. Administration of a representative iNKT cell ligand alpha-galactosylceramide (α-GalCer) or α-GalCer-pulsed APCs effectively stimulates iNKT cells and thereby induces antitumor effects. In this review, we will introduce the biology and importance of NKT cells in antitumor immunity. Previous studies have demonstrated that iNKT cells not only activate various immune cells but also reinvigorate exhausted immune cells in the tumor microenvironment. Furthermore, we will summarize the major clinical trials utilizing iNKT-based immunotherapies.

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References

  • Bae E-A, Seo H, Kim B-S, Choi J, Jeon I, Shin K-S, Koh C-H, Song B, Kim I-K, Min BS, Han YD, Shin SJ, Kang C-Y (2018) Activation of NKT cells in an anti-PD-1–resistant tumor model enhances antitumor immunity by reinvigorating exhausted CD8 T cells. Cancer Res 78:5315–5326

    Article  CAS  PubMed  Google Scholar 

  • Benlagha K, Kyin T, Beavis A, Teyton L, Bendelac A (2002) A thymic precursor to the NK T cell lineage. Science 296:553–555

    Article  CAS  PubMed  Google Scholar 

  • Chang DH, Osman K, Connolly J, Kukreja A, Krasovsky J, Pack M, Hutchinson A, Geller M, Liu N, Annable R (2005) Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med 201:1503–1517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang W-S, Kim J-Y, Kim Y-J, Kim Y-S, Lee J-M, Azuma M, Yagita H, Kang C-Y (2008) Cutting edge: programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol 181:6707–6710

    Article  CAS  PubMed  Google Scholar 

  • Cho JH (2017) Immunotherapy for non-small-cell lung cancer: current status and future obstacles. Immune Netw 17:378–391

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi C, Choi H, Lee J, Kang E, Cho D, Kim Y, Kim D, Seo H, Park M, Kim W, Oh T, Kang C-Y, Kim B-G (2018) 960P Phase I study of BVAC-C in HPV type 16 or 18 positive recurrent cervical carcinoma: safety, clinical activity and immunologic correlates. Ann Oncol 29(mdy285):168

    Google Scholar 

  • Chung Y, Kim B-S, Kim Y-J, Ko H-J, Ko S-Y, Kim D-H, Kang C-Y (2006) CD1d-restricted T cells license B cells to generate long-lasting cytotoxic antitumor immunity in vivo. Cancer Res 66:6843–6850

    Article  CAS  PubMed  Google Scholar 

  • Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, Smyth MJ, Godfrey DI (2007) IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J Immunol 178:2827–2834

    Article  CAS  PubMed  Google Scholar 

  • Coquet JM, Chakravarti S, Kyparissoudis K, Mcnab FW, Pitt LA, Mckenzie BS, Berzins SP, Smyth MJ, Godfrey DI (2008) Diverse cytokine production by NKT cell subsets and identification of an IL-17–producing CD4 − NK1. 1 − NKT cell population. Proc Natl Acad Sci USA 105:11287–11292

    Article  PubMed  PubMed Central  Google Scholar 

  • Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I, Kaneko Y, Koseki H, Kanno M, Taniguchi M (1997) Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science 278:1623–1626

    Article  CAS  PubMed  Google Scholar 

  • Exley M, Garcia J, Wilson SB, Spada F, Gerdes D, Tahir SM, Patton KT, Blumberg RS, Porcelli S, Chott A, Balk SP (2000) CD1d structure and regulation on human thymocytes, peripheral blood T cells, B cells and monocytes. Immunology 100:37–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Exley MA, Friedlander P, Alatrakchi N, Vriend L, Yue S, Sasada T, Zeng W, Mizukami Y, Clark J, Nemer D (2017) Adoptive transfer of invariant NKT cells as immunotherapy for advanced melanoma: a phase I clinical trial. Clin Cancer Res 23:3510–3519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gapin L, Matsuda JL, Surh CD, Kronenberg M (2001) NKT cells derive from double-positive thymocytes that are positively selected by CD1d. Nat Immunol 2:971

    Article  CAS  PubMed  Google Scholar 

  • Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, Von Blomberg BME, Scheper RJ, Van Der Vliet HJ, Van Den Eertwegh AJ (2002) A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 8:3702–3709

    CAS  PubMed  Google Scholar 

  • Godfrey DI, Berzins SP (2007) Control points in NKT-cell development. Nat Rev Immunol 7:505

    Article  CAS  PubMed  Google Scholar 

  • Godfrey DI, Macdonald HR, Kronenberg M, Smyth MJ, Van Kaer L (2004) NKT cells: what’s in a name? Nat Rev Immunol 4:231

    Article  CAS  PubMed  Google Scholar 

  • Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E (1997) CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278:1626–1629

    Article  CAS  PubMed  Google Scholar 

  • Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Sato H, Kondo E, Harada M, Koseki H, Nakayama T (1998) Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells. Proc Natl Acad Sci USA 95:5690–5693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim YJ, Ko HJ, Kim YS, Kim DH, Kang S, Kim JM, Chung Y, Kang CY (2008) α-Galactosylceramide-loaded, antigen-expressing B cells prime a wide spectrum of antitumor immunity. Int J Cancer 122:2774–2783

    Article  CAS  PubMed  Google Scholar 

  • Kim E-K, Jeon I, Seo H, Park Y-J, Song B, Lee K-A, Jang Y, Chung Y, Kang C-Y (2014a) Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis. Cancer Res 74:6705–6716

    Article  CAS  PubMed  Google Scholar 

  • Kim E, Seo H, Chae M, Jeon I, Song B, Park Y, Ahn H, Yun C, Kang CY (2014b) Enhanced antitumor immunotherapeutic effect of B-cell-based vaccine transduced with modified adenoviral vector containing type 35 fiber structures. Gene Ther 21:106

    Article  CAS  PubMed  Google Scholar 

  • Kitamura H, Iwakabe K, Yahata T, Nishimura S-I, Ohta A, Ohmi Y, Sato M, Takeda K, Okumura K, Van Kaer L (1999) The natural killer T (NKT) cell ligand α-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med 189:1121–1128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi E, Motoki K, Uchida T, Fukushima H, Koezuka Y (1995) KRN7000, a novel immunomodulator, and its antitumor activities. Oncol Res 7:529–534

    CAS  PubMed  Google Scholar 

  • Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14:561

    Article  CAS  PubMed  Google Scholar 

  • Mognol GP, Spreafico R, Wong V, Scott-Browne JP, Togher S, Hoffmann A, Hogan PG, Rao A, Trifari S (2017) Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc Natl Acad Sci USA 114:E2776–E2785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moreno M, Mol BM, Von Mensdorff-Pouilly S, Verheijen RH, Von Blomberg BME, Van Den Eertwegh AJ, Scheper RJ, Bontkes HJ (2008) Toll-like receptor agonists and invariant natural killer T-cells enhance antibody-dependent cell-mediated cytotoxicity (ADCC). Cancer Lett 272:70–76

    Article  CAS  PubMed  Google Scholar 

  • Motohashi S, Nagato K, Kunii N, Yamamoto H, Yamasaki K, Okita K, Hanaoka H, Shimizu N, Suzuki M, Yoshino I (2009) A phase I–II study of α-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol 182:2492–2501

    Article  CAS  PubMed  Google Scholar 

  • Nagato K, Motohashi S, Ishibashi F, Okita K, Yamasaki K, Moriya Y, Hoshino H, Yoshida S, Hanaoka H, Fujii S-I (2012) Accumulation of activated invariant natural killer T cells in the tumor microenvironment after α-galactosylceramide-pulsed antigen presenting cells. J Clin Immunol 32:1071–1081

    Article  CAS  PubMed  Google Scholar 

  • Nieda M, Okai M, Tazbirkova A, Lin H, Yamaura A, Ide K, Abraham R, Juji T, Macfarlane DJ, Nicol AJ (2004) Therapeutic activation of Vα24+ Vβ11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103:383–389

    Article  CAS  PubMed  Google Scholar 

  • Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parekh VV, Wilson MT, Olivares-Villagómez D, Singh AK, Wu L, Wang C-R, Joyce S, Van Kaer L (2005) Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest 115:2572–2583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, Kumar V, Wu L, Van Kaer L (2009) PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. J Immunol 182:2816–2826

    Article  CAS  PubMed  Google Scholar 

  • Pauken KE, Wherry EJ (2015) Overcoming T cell exhaustion in infection and cancer. Trends Immunol 36:265–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359:1350–1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Semmling V, Lukacs-Kornek V, Thaiss CA, Quast T, Hochheiser K, Panzer U, Rossjohn J, Perlmutter P, Cao J, Godfrey DI (2010) Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat Immunol 11:313

    Article  CAS  PubMed  Google Scholar 

  • Seo H, Jeon I, Kim B-S, Park M, Bae E-A, Song B, Koh C-H, Shin K-S, Kim I-K, Choi K, Oh T, Min J, Min BS, Han YD, Kang S-J, Shin SJ, Chung Y, Kang C-Y (2017) IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours. Nat Commun 8:15776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seo H, Kim B-S, Bae E-A, Min BS, Han YD, Shin SJ, Kang C-Y (2018) IL21 therapy combined with PD-1 and Tim-3 blockade provides enhanced NK cell antitumor activity against MHC class I-deficient tumors. Cancer Immunol Res 6:685–695

    Article  CAS  PubMed  Google Scholar 

  • Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161:205–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smyth MJ, Godfrey DI (2000) NKT cells and tumor immunity—a double-edged sword. Nat Immunol 1:459

    Article  CAS  PubMed  Google Scholar 

  • Sullivan BA, Kronenberg M (2005) Activation or anergy: NKT cells are stunned by α-galactosylceramide. J Clin Invest 115:2328–2329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taraban VY, Martin S, Attfield KE, Glennie MJ, Elliott T, Elewaut D, Van Calenbergh S, Linclau B, Al-Shamkhani A (2008) Invariant NKT cells promote CD8+ cytotoxic T cell responses by inducing CD70 expression on dendritic cells. J Immunol 180:4615–4620

    Article  CAS  PubMed  Google Scholar 

  • Terabe M, Swann J, Ambrosino E, Sinha P, Takaku S, Hayakawa Y, Godfrey DI, Ostrand-Rosenberg S, Smyth MJ, Berzofsky JA (2005) A nonclassical non-Vα14 Jα18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. J Exp Med 202:1627–1633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wherry EJ (2011) T cell exhaustion. Nat Immunol 12:492

    Article  CAS  PubMed  Google Scholar 

  • Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon R-A, Reed K (2013) Nivolumab plus ipilimumab in advanced melanoma. New Engl J Med 369:122–133

    Article  CAS  PubMed  Google Scholar 

  • Yamasaki K, Horiguchi S, Kurosaki M, Kunii N, Nagato K, Hanaoka H, Shimizu N, Ueno N, Yamamoto S, Taniguchi M (2011) Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin Immunol 138:255–265

    Article  CAS  PubMed  Google Scholar 

  • Zhou D, Mattner J, Cantu C, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu Y-P, Yamashita T (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306:1786–1789

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Basic Science Research Program (NRF-2015R1A2A1A10055844) and the Bio & Medical Technology Development Program (NRF-2016M3A9B5941426).

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Correspondence to Chang-Yuil Kang.

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Bae, EA., Seo, H., Kim, IK. et al. Roles of NKT cells in cancer immunotherapy. Arch. Pharm. Res. 42, 543–548 (2019). https://doi.org/10.1007/s12272-019-01139-8

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