Immune Networks and Therapeutic Targeting of iNKT Cells in Cancer

doi:10.1016/j.it.2019.09.008

Trends in Immunology

Volume 40, Issue 11, November 2019, Pages 984-997

https://doi.org/10.1016/j.it.2019.09.008 Get rights and content

Highlights

iNKT cell subsets differentiate in the thymus, and iNKT1 cells can play a role in immune surveillance against cancer.
Once optimally activated, iNKT1 cells can exert antitumor effects in peripheral tissues.
Following activation, memory iNKT cells can differentiate in peripheral organs.
Strategies using iNKT cell-licensed dendritic cells may constitute a promising new tool for immune enhancement in cancer immunotherapies.

One of the primary goals in tumor immunotherapy is to reset the immune system from tolerogenic to immunogenic – a process in which invariant natural killer T (iNKT) cells are implicated. iNKT cells develop in the thymus and perform immunosurveillance against tumor cells peripherally. When optimally stimulated, iNKT cells differentiate and display more efficient immune functions. Some cells survive and act as effector memory cells. We discuss the putative roles of iNKT cells in antitumor immunity, and posit that it may be possible to develop novel therapeutic strategies to treat cancers using iNKT cells. In particular, we highlight the challenge of uniquely energizing iNKT cell-licensed dendritic cells to serve as effective immunoadjuvants for both arms of the immune system, thus coupling immunological networks.

Section snippets

Eliciting Type I Invariant NKT Cells (iNKTs) in Cancer Immunotherapy

One barrier to effective tumor immunotherapy is the tolerogenic state that is created in cancer patients through the action of tumor cells or immunoregulatory cells (e.g., regulatory T cells and tumor-associated macrophages). Hence, to ‘reset’ the immune system from tolerogenic to immunogenic would seem to be a key factor in facilitating immunotherapy. Natural killer T (NKT) cells may be a candidate target for manipulation: these cells are tissue-homing and tissue-resident; they also play

NKT Cell Types

NKT cells are categorized into types I and II. Type I are known as iNKT cells that express an invariant T cell receptor (TCR) formed by the rearrangement of Vα14 and Jα18 TCRα gene segments paired preferentially with a diverse rearrangement involving the Vβ8.2, Vβ7, and Vβ2 TCRβ gene segments in mice 3, 4, 5. In humans, iNKT cells express a Vα24–Jα18 rearranged TCRα chain associated with a Vβ11 TCRβ chain [5]. Although the frequency of iNKT cells in healthy donors is low in peripheral blood

iNKT Cell Development in the Murine Thymus

The development of iNKT cell subsets in the thymus was recently reported in detail [11]. Both intrinsic and extrinsic cellular factors have been shown to affect iNKT cell development. Specific intrinsic factors include iNKT TCR signaling and the regulation of transcription factor expression and epigenetics (see below) 11, 14, 15, 16, 17, 18, 19, 20. The TCR must be engaged by CD1d, as evidenced by iNKT cells that fail to differentiate in the thymus of CD1d^−/− mice [21]. Murine iNKT cell

iNKT Cell Effector Function in Immunosurveillance against Malignancies

The frequency and function of iNKT cells in the tumor or in the circulation can be selectively and highly correlated with overall survival in numerous human cancers 38, 39, 40, 41, 42, 43, 44, 45, 46. Moreover, an antitumor immunosurveillance role has been tested for iNKT cells in several murine models (CD1d KO or Jα18 KO mice). Specifically, the carcinogen methylcholanthrene (MCA) has been shown to initiate the growth of spontaneous tumors more rapidly and progressively in Jα18 KO mice than in

Optimal Conditions for Effective Activation of iNKT Cells against Tumors

Glycolipids are recognized by iNKT cells. The first glycosphingolipid ligand discovered for iNKT cells was α-GalCer [56]: the α-linked glycan in α-GalCer can directly and potently activate iNKT cells in vitro [57] (Table 1). Upon activation, iNKT cells produce large amounts of IFN-γ and IL-4 [2]. Simultaneously, they can exert cytotoxic effects against tumor cells via perforin/granzyme and FasL [58]. However, iNKT1 cells need to be activated. For optimal activation of iNKT cells with cytotoxic

iNKT Cell-Imprinted Function of NK cells (the iNKT–NK Cell Axis)

A relationship between iNKT cells and the biological features of NK cells has been demonstrated (Figure 1): following activation of iNKT cells, high-functioning NK cells can be imprinted to exhibit antitumor effects in murine models 68, 69. Moreover, when healthy human PBMCs were stimulated by α-GalCer-loaded, CD1d⁺ cells, activated iNKT cells and NK cells were also detected [69]. In fact, the expression of NKG2D on CD56^dimCD16⁺ NK cells and DNAX-activating molecule 1 (DNAM-1) on CD56^brightCD16⁻

Downstream Signaling of DCs by iNKT Cell Licensing in situ as a Potential Immunoadjuvant Role for Antitumor-Specific CTL Induction

In the steady state, DCs in situ are immature. Following stimulation, DC maturation leads to conversion from tolerogenic to immunogenic adaptive immune responses [71]. In fact, when the antigen and iNKT cell ligand are coadministered into C57BL/6 mice, antigen-specific CD4⁺ and CD8⁺ T cells are generated via DC maturation in situ 72, 73 (Figure 1), thereby promoting upregulation of MHC class II and co-stimulatory receptors (CD40, CD80, and CD86) at an early phase, and upregulation of CD70 and

Conventional Autologous α-GalCer-Pulsed DC Therapy and Putative Next-Generation iNKT-Mediated Therapeutic Strategies against Cancers

Recent studies in clinical immunotherapy have provided significant insights into the role of DCs and various T cell subsets. Several studies have reported a low number of iNKT cells among the PBMCs of patients with various cancers, including colorectal cancer, melanoma, non-small-cell lung cancer (NSCLC), myelodysplastic syndromes (MDS), and multiple myeloma (MM) 69, 82. Generally, most iNKT cells do not usually circulate at steady-state, but instead reside in organs (Table 1) [83]. Therefore,

Concluding Remarks

iNKT cells are a multifunctional cell population that executes immunosurveillance and plays a role in the defense and clearance of cancer cells and infectious diseases. Hence, iNKT cells have been implicated in the process of shifting from tolerogenic to immunogenic states. This surveillance function is evident in steady-state iNKT cells without prior sensitization; however, restoring or energizing iNKT cells might be useful in complementing or potentiating antitumor immunotherapies.

Acknowledgments

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI grant JP19K07653 (to S.F.).

Glossary

Adjuvants: immune potentiators or immunomodulators that enhance the adaptive immune response to vaccine antigens.
Anergy: a tolerance mechanism in which lymphocytes are intrinsically functionally inactivated following an antigen encounter. Anergic cells exhibit low IL-2 production but are long-lived in a hyporesponsive state.
Antibody-dependent cellular cytotoxicity (ADCC): immune mechanism through which Fc receptor-bearing effector cells can recognize and kill antibody-coated target cells.
Chimeric

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Trends in Immunology

OpinionImmune Networks and Therapeutic Targeting of iNKT Cells in Cancer

Highlights

Section snippets

Eliciting Type I Invariant NKT Cells (iNKTs) in Cancer Immunotherapy

NKT Cell Types

iNKT Cell Development in the Murine Thymus

iNKT Cell Effector Function in Immunosurveillance against Malignancies

Optimal Conditions for Effective Activation of iNKT Cells against Tumors

iNKT Cell-Imprinted Function of NK cells (the iNKT–NK Cell Axis)

Downstream Signaling of DCs by iNKT Cell Licensing in situ as a Potential Immunoadjuvant Role for Antitumor-Specific CTL Induction

Conventional Autologous α-GalCer-Pulsed DC Therapy and Putative Next-Generation iNKT-Mediated Therapeutic Strategies against Cancers

Concluding Remarks

Acknowledgments

Glossary

Immunity

Curr. Opin. Immunol.

Mol. Immunol.

Immunity

Immunity

Curr. Opin. Immunol.

Blood

Clin. Immunol.

Clin. Immunol.

Mucosal. Immunol.

Tetrahedron

Curr. Opin. Immunol.

Clin. Immunol.

Immunity

Immunity

Blood

Trends Immunol.

Blood

Immunity

Blood

Cell. Rep.

Lung Cancer

Clin. Immunol.

Tissue-specific functions of invariant natural killer T cells

Nat. Rev. Immunol.

Exploiting antitumor immunotherapeutic novel strategies by deciphering the cross talk between invariant NKT cells and dendritic cells

Front Immunol.

Innate Valpha14+ natural killer T cells mature dendritic cells, leading to strong adaptive immunity

Immunol. Rev.

An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4−8− T cells in mice and humans

J. Exp. Med.

An invariant Va24-JaQ/Vb11 T cell receptor is expressed in all individuals by clonally expanded CD4−8− T cells

J. Exp. Med.

High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens

J. Exp. Med.

Evaluation of the function of human invariant NKT cells from cancer patients using α-galactosylceramide-loaded murine dendritic cells

J. Immunol.

Possible therapeutic application of targeting type II natural killer T cell-mediated suppression of tumor immunity

Front. Immunol.

Prolonged interferon-γ producing NKT response induced with α-galactosylceramide-loaded dendritic cells

Nat. Immunol.

KLRG+ invariant natural killer T cells are long-lived effectors

Proc. Natl. Acad. Sci. U. S. A.

The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions

Nat. Immunol.

The gene encoding early growth response 2, a target of the transcription factor NFAT, is required for the development and maturation of natural killer T cells

Nat. Immunol.

Development and function of invariant natural killer T cells producing Th2- and Th17-cytokines

PLoS Biol.

Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation

J. Exp. Med.

The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

Nat. Immunol.

Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function

Proc. Natl. Acad. Sci. U. S. A.

A thymic precursor to the NK T cell lineage

Science

A natural killer T (NKT) cell developmental pathway involving a thymus-dependent NK1.1−CD4+ CD1d-dependent precursor stage

J. Exp. Med.

Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells

Nat. Immunol.

Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling

Nat. Immunol.

TCR signal strength controls thymic differentiation of iNKT cell subsets

Nat. Commun.

Opinion
Immune Networks and Therapeutic Targeting of iNKT Cells in Cancer

Innate Valpha14⁺ natural killer T cells mature dendritic cells, leading to strong adaptive immunity

An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4⁺ and CD4⁻8⁻ T cells in mice and humans

An invariant Va24-JaQ/Vb11 T cell receptor is expressed in all individuals by clonally expanded CD4⁻8⁻ T cells

KLRG⁺ invariant natural killer T cells are long-lived effectors

A natural killer T (NKT) cell developmental pathway involving a thymus-dependent NK1.1⁻CD4⁺ CD1d-dependent precursor stage

Alternative pathway for the development of Valpha14⁺ NKT cells directly from CD4⁻CD8⁻ thymocytes that bypasses the CD4⁺CD8⁺ stage