Roles of NKT cells in cancer immunotherapy
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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.
KeywordsInvariant natural killer T (iNKT) cell Cancer immunotherapy Alpha-galactosylceramide (α-GalCer) CD1d Tumor immunology
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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Conflict of interest
All authors declare no potential conflicts of interest.
- 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 78:5315–5326CrossRefPubMedGoogle 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 201:1503–1517CrossRefPubMedGoogle 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):168Google 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 105:11287–11292CrossRefPubMedGoogle 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 189:1121–1128CrossRefPubMedGoogle 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 272:70–76CrossRefPubMedGoogle 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 182:2492–2501CrossRefPubMedGoogle 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 32:1071–1081CrossRefPubMedGoogle 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 103:383–389CrossRefPubMedGoogle 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 8:15776CrossRefPubMedGoogle 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 202:1627–1633CrossRefPubMedGoogle Scholar