What is nkt cells

Scand J Immunol 76 3 — Terabe M, Berzofsky JA. Cancer Immunol Immunother 63 3 — Macho-Fernandez E, Brigl M. Dasgupta S, Kumar V.

Immunogenetics 68 8 — Dhodapkar MV, Kumar V. J Immunol 3 — Adv Immunol — Activation strategies for invariant natural killer T cells. The transcriptional programs of iNKT cells. Semin Immunol 27 1 — Brigl M, Brenner MB. CD1: antigen presentation and T cell function. The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian alpha-linked glycosylceramides.

Immunity 41 4 — Agelasphins, novel a-galactosylceramides from the marine sponge Agelas mauritianus. Tetrahedron Lett —2. Structure-activity relationship of alpha-galactosylceramides against Bbearing mice. J Med Chem 38 12 — Science —9. Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-galactosylceramide. J Exp Med 11 — A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells.

Nature —4. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 1—2 — PLoS Biol 11 7 :e Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature —9. Recognition of bacterial glycosphingolipids by natural killer T cells.

Nature —5. Eur J Immunol 35 6 — Invariant natural killer T cells recognize a fungal glycosphingolipid that can induce airway hyperreactivity. Nat Med 19 10 — Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity.

J Clin Invest 1 — J Immunol 2 — Quantitative and qualitative differences in the in vivo response of NKT cells to distinct alpha- and beta-anomeric glycolipids. J Immunol 6 — Lysosomal glycosphingolipid recognition by NKT cells. Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 7 9 — Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria.

Nat Immunol 12 10 — Immunity 34 3 — Murine CD1d-restricted T cell recognition of cellular lipids. Immunity 12 2 — Peroxisome-derived lipids are self antigens that stimulate invariant natural killer T cells in the thymus. Nat Immunol 13 5 — Recognition of lyso-phospholipids by human natural killer T lymphocytes.

PLoS Biol 7 10 :e Characterization and functional analysis of mouse semi-invariant natural T cells. Curr Protoc Immunol — NKT cell ligand recognition logic: molecular basis for a synaptic duet and transmission of inflammatory effectors. J Immunol 3 —9. CD1d-restricted glycolipid antigens: presentation principles, recognition logic and functional consequences. Expert Rev Mol Med e Mechanism of CD1d-restricted natural killer T cell activation during microbial infection.

Nat Immunol 4 12 —7. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med 6 — Innate recognition of cell wall beta-glucans drives invariant natural killer T cell responses against fungi.

Cell Host Microbe 10 5 — The biology of NKT cells. Glucosylceramide synthase is involved in development of invariant natural killer T cells. Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. Immunity 27 4 — J Immunol 3 —4. Immunol Cell Biol 84 1 —9. Interleukin and natural killer and NKT cells play a critical role in innate protection against genital herpes simplex virus type 2 infection.

J Virol 77 18 — Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 14 6 — J Virol 76 9 — Interleukin is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages.

J Biol Chem 12 — J Immunol 10 — Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest 12 — Activation of invariant NKT cells enhances the innate immune response and improves the disease course in influenza A virus infection. Eur J Immunol 38 7 — Pivotal advance: invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune-pathology during severe influenza A virus infection.

J Leukoc Biol 91 3 — Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nat Med 18 7 —8. Nagarajan NA, Kronenberg M. Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J Immunol 5 — The mechanism of invariant NKT cell responses to viral danger signals. J Immunol 7 —6. PLoS Pathog 4 7 :e J Exp Med 5 — Another view of T cell antigen recognition: cooperative engagement of glycolipid antigens by Va14Ja18 natural T iNKT cell receptor [corrected].

J Immunol 9 — Granulocyte-macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny. Immunity 25 3 — Blood 17 — Nat Rev Immunol 5 1 — Mashayekhi M, et al. Immunity 35 2 — Distinct roles of dendritic cells and B cells in Va14Ja18 natural T cell activation in vivo.

J Immunol 8 — Distinct APCs explain the cytokine bias of alpha-galactosylceramide variants in vivo. J Immunol 7 — Nat Immunol 3 9 — A single subset of dendritic cells controls the cytokine bias of natural killer T cell responses to diverse glycolipid antigens.

Immunity 40 1 — PLoS One 6 10 :e J Immunol 2 —9. Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor. Nat Immunol 6 8 —8.

Activation of natural killer T cells by alpha-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J Exp Med 2 — J Exp Med 12 — CD1-dependent dendritic cell instruction. Nat Immunol 3 12 —8. Cutting edge: cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. PubMed Abstract Google Scholar.

J Immunol 5 —7. Google Scholar. The natural killer T NKT cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin IL production by dendritic cells and IL receptor expression on NKT cells.

J Exp Med 7 —8. J Immunol 11 — Chaudhry MS, Karadimitris A. Role and regulation of CD1d in normal and pathological B cells. J Immunol 10 —8. The CD1d-binding glycolipid alpha-galactosylceramide enhances humoral immunity to T-dependent and T-independent antigen in a CD1d-dependent manner. Immunology 1 — NKT-cell help to B lymphocytes can occur independently of cognate interaction.

Blood 2 —6. NK T cells provide lipid antigen-specific cognate help for B cells. Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an ILdependent manner. Nat Immunol 13 1 — B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo.

Identification of Bcldependent follicular helper NKT cells that provide cognate help for B cell responses. Nat Immunol 11 4 — Cell Rep 16 7 —9. Discovering naturally processed antigenic determinants that confer protective T cell immunity. J Clin Invest 5 — J Immunol 10 —7. Immunol Lett 1 — Invariant natural killer T cells: innate-like T cells with potent immunomodulatory activities. Tissue Antigens 73 6 — Invariant NK T cells: potential for immunotherapeutic targeting with glycolipid antigens.

Immunotherapy 3 1 — Natural killer T cell anergy, co-stimulatory molecules and immunotherapeutic interventions. Hum Immunol 75 3 — Optimizing NKT cell ligands as vaccine adjuvants. Immunotherapy 6 3 — Nair S, Dhodapkar MV. Natural killer T cells in cancer immunotherapy. A brief review of clinical trials involving manipulation of invariant NKT cells as a promising approach in future cancer therapies.

Cent Eur J Immunol 42 2 — Cancer Immunol Res 2 1 — J Immunol 5 —9. Cancer Immunol Immunother 51 1 :1—8. CD1d expression level in tumor cells is an important determinant for anti-tumor immunity by natural killer T cells. Leuk Lymphoma 47 10 — Differential antitumor immunity mediated by NKT cell subsets in vivo. J Exp Med 9 — Reciprocal crosstalk between dendritic cells and natural killer T cells: mechanisms and therapeutic potential.

CD1d-restricted T cells license B cells to generate long-lasting cytotoxic antitumor immunity in vivo. Cancer Res 66 13 — Int J Cancer 12 — Clin Immunol NKT cells as an ideal anti-tumor immunotherapeutic. Science —6. Int J Cancer 7 — J Exp Med 4 —8. J Immunol 4 — Combination therapy of in vitro-expanded natural killer T cells and alpha-galactosylceramide-pulsed antigen-presenting cells in patients with recurrent head and neck carcinoma.

Cancer Sci 6 —8. Invariant natural killer T cells in immune regulation of blood cancers: harnessing their potential in immunotherapies. Bendelac A. J Exp Med 6 —6. J Immunol 5 —8. Distinct roles for signals relayed through the common cytokine receptor gamma chain and interleukin 7 receptor alpha chain in natural T cell development. J Exp Med 2 —6. In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers.

Nat Rev Immunol 4 3 —7. A thymic precursor to the NK T cell lineage. Science —5. J Exp Med 7 — An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells. Nat Immunol 11 3 —9. Genetic evidence supporting selection of the Valpha14i NKT cell lineage from double-positive thymocyte precursors.

Immunity 22 6 — Nat Immunol 11 5 — NKT cells derive from double-positive thymocytes that are positively selected by CD1d. Nat Immunol 2 10 —8. Control points in NKT-cell development. Importantly, Sag et al. Since this approach has not been used in NKT phenotype studies yet, no information is available on the phenotype of the different functional NKT cell subsets. This might indicate that these NKT cells have been sensitized and activated during fetal life by encountering a natural ligand 69 , which contributes to the ability of NKT cells to respond fast upon meeting the antigen.

This downregulation could be related to the fact that NKT cells already constitute a memory phenotype and, therefore, do not require CD27 to generate NKT cell immunity and maturation upon first antigen encounter. In addition to the expression of NK- and T cell-associated cell surface markers, type I NKT cells express a wide range of inducible cytokine- and chemokine receptors enabling them to respond to various signals 28 — 31 , 79 — Finally, type I NKT cells express various markers that are involved in a wide range of functionalities such as granzyme B, perforin, and CD95L, which play important roles in cytotoxicity 29 , 31 , However several mouse models have been developed to study the role of type II NKT cells in cancer in vivo.

However, this approach has not been widely used due to the unstable nature of sulfatide-loaded CD1d complexes. As a result, the phenotype and function of type II NKT cells remain largely elusive, and new methods are essential to characterize this cell population in further detail.

Exceptions are killer-cell Ig-like receptors KIRs that provide either inhibitory or stimulatory signals upon interaction with human leukocyte antigen HLA molecules 31 , 95 , Studies so far suggest that the expression levels of cell surface markers on type I NKT cells are highly variable among healthy individuals. These phenotypical modulations adapt the functional capabilities of the NKT cells, including the production of specific cytokines upon activation.

Studies on human NKT cells are needed to support this hypothesis. CD1d is primarily expressed by antigen-presenting cells APC but has also been reported to be expressed by some epithelial, parenchymal, and vascular smooth muscle cells 98 , Exogenous microbial- and non-microbial-derived glycolipids enter APC via different mechanisms as thoroughly reviewed by Bendelac et al.

For instance, exogenous glycolipids can be captured by the mannose receptor, or alternatively, insert themselves directly into the cell membrane of APC, upon which they undergo endocytosis.

Furthermore, exogenous glycolipids may enter APC with very low-density lipoprotein particles via the low-density lipoprotein LDL receptor, or via phagocytosis. Finally, scavenger receptors can mediate internalization of apoptotic cells and modified LDL, which also leads to entering of exogenous glycolipids into APC. During endosomal trafficking, CD1d molecules relocate from the cell membrane toward a late endosome where the bound glycolipids are removed from CD1d and replaced by new glycolipids Figure 2 , Thereafter, the CD1d molecules relocate back to the cell membrane.

For instance, activation of nucleotide-binding oligomerization domain-1 and -2 intracellular pattern recognition receptors by bacteria, or activation of formyl peptide receptor 2 by serum amyloid A-1, results in loading of endogenous glycolipids into CD1d molecules during endosomal CD1d trafficking Figure 2 , Furthermore, toll-like receptor signaling upon stimulation with lipopolysaccharide was suggested to result in the loading of endogenous glycolipids into CD1d molecules , The exact mechanism of how these signaling pathways lead to the loading of endogenous glycolipids into CD1d is, however, unknown.

Figure 2. CD1d-presented glycolipids in APC. APC present exogenous and endogenous glycolipids in the context of CD1d. During endosomal trafficking, CD1d molecules relocate from the cell membrane toward a late endosome where the bound glycolipid antigens are removed from CD1d and replaced by new glycolipid antigens. Exogenous glycolipids indicated in blue enter the APC late endosome via endocytosis or phagocytosis 1. The exogenous and endogenous glycolipids are loaded into CD1d molecules upon which they relocate back to the cell membrane.

Crowe et al. Due to their memory-activated phenotype 69 , NKT cells have the ability to respond quickly upon encountering an antigen. NKT cells seem to behave similar to NK cells when it comes to their activation. As discussed earlier, phenotype studies showed that NKT cells also express a wide range of these receptors 27 — When the balance of signals is shifted toward activation, an NKT cell is activated, resulting in cytokine production as well as direct killing of tumor cells in a CD1d-independent manner Figure 3.

In addition, a part of the NKT cell population expresses the low affinity Fc receptor CD16 which is known to induce antibody-dependent cytotoxicity when present on NK cells This phenomenon has, however, not been studied as yet in relation to NKT cells. In conclusion, NKT cells can be activated via different NK- and T cell-associated mechanisms that lead to immediate killing of tumor cells and secretion of large amounts of cytokines that have a major influence on the immune system.

Figure 3. Activation of NKT cells. Activation of NKT cells is dependent on a balance between activating and inhibitory signals. When the balance is skewed toward activation, NKT cells produce and secrete high amounts of cytokines.

These cytokines are secreted by, i. This resembles the response of conventional T cells upon activation in the TME in presence of coinhibitory stimuli or checkpoint molecules like programmed death-ligand 1 PD-L1 , This is most likely a feedback mechanism used by NKT cells to prevent tissue damage. Depending on which functional NKT cell subsets are involved, both type I and type II NKT cell subsets are able to either skew the immune response toward inflammation or toward tolerance.

Activated NKT cells shape the TME via modulation of cells from both the innate and adaptive immune system Figure 4 , thereby implementing an important regulatory function.

Figure 4. The regulatory function of activated NKT cells. Upon activation, NKT cells have a major influence on other immune cells. Activated T cells interact with B cells resulting in their activation, as well as production of immunoglobulins and affinity maturation. In addition, NKT cells can reverse the phenotype of immune suppressive neutrophils. Upon activation, NKT cells are also able to activate NK cells and macrophages and induce a functional shift of monocytes toward a DC-like phenotype.

NKT cells are unique in the sense that they can activate and induce full maturation of DC , , NKT cells are also able to reverse the phenotype of immune suppressive neutrophils by reducing secretion of IL and enhancing IL production in a CD1d-dependent manner In conclusion, NKT cells are able to rapidly respond to a wide variety of glycolipids and stress proteins using T- and NK cell-like mechanisms, respectively. Although NKT cells comprise a minor immune cell subset in most organs, they have a major effect on immune regulation since they can skew an immune response toward inflammation or tolerance in a very short time by secreting pro- or anti-inflammatory cytokines.

Besides, NKT cells have the ability to kill tumor cells directly upon activation but, probably reflected by their relative low numbers, NKT cells primarily have a regulatory function. Based on this information, it is clear that NKT cells are not just cells with NK- and T cell properties: by combining characteristics of both cell types, NKT cells are able to add unique functions to the immune response.

NKT cells may play a uniquely central role during the very first steps in the initiation of an antitumor immune response. The main reasons are the ability of NKT cells to respond fast by influencing other immune cells, resulting in amplification or dampening of the immune response.

Thereafter, studies showed that type I NKT cells were the key effectors of antitumor responses in a murine B melanoma metastasis model — For instance, Toura et al.

By contrast, mice lacking type I NKT cells were more prone to chemical or p53 loss-induced tumor development — Recently, it was reported that type I NKT cells also play a role in preventing metastatic disease in a 4T1 mammary carcinoma model Smyth et al. After the discovery of the important role of activated type I NKT cells in antitumor responses in vivo , studies focused on the mechanisms used by these NKT cells to eradicate tumor cells.

As mentioned earlier, CD1d is primarily expressed by APC, although malignant hematopoietic cells have also been reported to express CD1d on their cell membrane 4 , — In addition, there is evidence that solid tumors also express CD1d, including renal cell and colorectal carcinomas , To kill tumor cells directly via CD1d interaction, they need to present glycolipids that can be recognized by NKT cells.

There is evidence from murine studies that type I NKT cells can be activated by tumor-derived glycolipids that are cross-presented by APC in the context of CD1d — However, until now, the nature of tumor glycolipids that are recognized by NKT cells remains poorly elucidated. Moreover, although type I NKT cells are capable of killing tumor cells directly, they primarily mediate antitumor activity via the activation of downstream immune effector cells as demonstrated by human and mouse studies 4 , , , However, some in vivo models provided important information.

Injections with sulfatide increased the number of tumor nodules in a CT26 colon carcinoma lung metastasis mouse model via activation of type II NKT cells A role for MDSC in inhibition of antitumor immunosurveillance was supported by the study of Renukaradhya et al. This implicates an important role for type II NKT cells in suppression of immunosurveillance in cancer. Although Zhao et al. Here, we will focus on both tumor-infiltrating and -circulating NKT cells. Studies showed a difference in the presence of NKT cells between tumor tissue and non-tumor tissue.

The frequency of type I NKT cells was reported to be higher in intrahepatic malignant tumors and colorectal carcinomas compared with normal liver tissue and normal mucosa, respectively , The opposite pattern was reported by Kenna et al.

In addition, several studies showed a correlation between infiltrating NKT cell numbers and clinical outcome. High numbers of tumor-infiltrating type I NKT cells correlated with a relatively good clinical outcome in patients diagnosed with colorectal cancer and neuroblastoma , Accordingly, absence of infiltrating type I NKT cells and low numbers of infiltrating NKT-like cells correlated with poor patient survival and disease progression in neuroblastoma and gastric cancer, respectively 91 , The function and phenotype of infiltrating type I NKT cells was addressed in studies on hepatocellular carcinoma, colorectal cancer, and neuroblastoma 35 , , In addition, in a study on colorectal cancer, expression of the activation markers CD69L and FasL was reported on a larger fraction of infiltrating type I NKT cells in tumor tissue compared with normal mucosa In addition, it was observed that type I NKT cell infiltration in neuroblastomas was associated with CCL2 expression on tumor cells, indicating that expression of homing receptors on tumors was essential for infiltration of type I NKT cells in neuroblastoma Furthermore, in two studies 91 , 92 the function and phenotype of infiltrating NKT-like cells in tumors were described.

Peng et al. In conclusion, tumor-infiltrating type I NKT cells and NKT-like cells may express less activating receptors, homing receptors and proliferation markers and produce lower amounts of T H 1-associated cytokines compared with type I NKT cells and NKT-like cells in healthy tissue, indicating tolerance and not antitumor activity. In addition, studies also showed altered function of circulating type I NKT cells in cancer patients. For instance, the number of circulating type I NKT cells was significantly decreased in patients with different cancers compared with healthy controls — In line with the results on infiltrating type I NKT cells, low circulating type I NKT cell numbers correlated with poor clinical outcome in patients with head and neck squamous cell carcinoma , Interestingly, late-stage cancer patients presented with lower type I NKT cell numbers than early-stage cancer patients with oral squamous cell carcinoma or laryngeal cancer , , suggesting cancer-mediated depletion of NKT cells.

After resection of the primary tumor, type I NKT cell numbers did not increase in patients with different cancer types , By contrast, circulating NKT-like cell numbers were not decreased in patients diagnosed with laryngeal cancer, gastric cancer, or hepatocellular carcinoma 91 , 92 , Besides being reduced in numbers, circulating type I NKT cells are often functionally impaired in patients , , , — For instance, circulating type I NKT cells derived from patients with prostate cancer or oral squamous cell carcinoma had a T H 2-biased cytokine profile , In conclusion, reduced frequency of circulating NKT cells and altered phenotype, resulting in altered function, of both infiltrating and circulating NKT cells are often observed in cancer patients, especially in patients with late-stage disease.

As discussed earlier, T H 1-like NKT cells are promising candidates to initiate effective antitumor immune responses. For instance, they have been reported to colocalize with tumor-associated macrophages TAM with an M2-polarized phenotype that promote tumor growth and progression , This colocalization resulted in CD1d-dependent killing of TAM that cross-presented tumor-derived glycolipids in vivo , Finally, Courtney et al.

On the other side, an immature tolerogenic DC subset has been described that produces reduced amounts of IL and high amounts of IL, resulting in an immunosuppressive TME In this way, immune escape of tumor cells might be prevented. In addition, as discussed earlier, tumors have been reported to express CD1d on their cell membrane , and might therefore be killed in a CD1d-dependent manner.

HLA class I loss or downregulation has often been reported in tumors including carcinomas, sarcomas, neuroblastomas, and melanomas — NKT cells may have, however, primarily a regulatory function, suggesting that the antitumor activity mediated by direct killing of tumor cells is of lesser importance.

Figure 5. The dual role of NKT cells in cancer. During early tumor development, T H 1-like NKT cells may induce an effective antitumor response via direct killing of tumor cells upon interaction with stress proteins and CD1d molecules, respectively. However, overstimulated NKT cells produce large amounts of immunosuppressive cytokines, resulting in a net effect of immunosuppression. Receptors that are known to be involved in NKT cell-mediated antitumor responses are indicated in the figure.

As discussed in the previous chapter, the phenotype and function of T H 1-like subsets is frequently altered in patients. The NKT cell population in patients is skewed toward a T H 2 profile, proliferative impaired and, in addition, reduced in size.

During cancer progression, NKT cells may be exposed to chronic stimulation, which is known to induce anergy and skew NKT cells toward immunosuppressive subsets. Based on this hypothesis, we propose that T H 1-like NKT cells induce an effective antitumor response during early tumor development and perhaps prevent further tumor development in many cases.

However, in some cases, at some point during tumor progression, NKT cells become overstimulated. In conclusion, we discussed evidence supporting our hypothetical model Figure 5 that T H 1-like NKT cells are responsible for initiating effective antitumor immune responses during early tumor development. When NKT cells become overstimulated and anergic due to tumor progression, a part of the NKT cell population is deleted in cancer patients.

In addition, the remaining NKT cells lose their antitumor function and start facilitating immune escape and tumor progression. In summary, we illustrated three problems regarding NKT cells in cancer patients. First, the numbers are lower compared with healthy individuals. Second, NKT cells are often anergic in cancer patients. Because of their potential to induce effective antitumor responses in vivo , several NKT cell-based immunotherapies in humans have been developed over the past years as thoroughly reviewed by Nair and Dhodapkar These immunotherapies primarily focused on activation and expansion of the type I NKT cell population.

For instance, a phase I clinical trial was executed in which intravenous i. Although not investigated in details in this study, recovery of NKT cell numbers was not observed within a week.

These injections resulted in expansion of the type I NKT cell population in some patients — For instance, Chang et al. Treatment did, however, not result in a clinical tumor response in the majority of patients — In addition, a phase II study reported stable disease in 5 of 17 patients with non-small cell lung cancer NSCL upon i.

These data indeed indicate a crucial role for T H 1-like type I NKT cells in antitumor immune responses and emphasize the essential need for expansion of this NKT cell population in cancer patients. Hence, immunotherapeutic approaches focused on skewing NKT cells toward a T H 1 profile should be developed. In this therapy, PBMC obtained from the patient, i.

Thereafter, the ex vivo -activated type I NKT cells were administered to the patients. Tumor regression and stable disease were reported in 10 of 10 of these patients These clinical responses did, however, not correlate with the induction of immunological responses in blood i. Treatment was well tolerated and resulted in stable disease in 2 of 9 NSCL patients and 3 of 9 patients with advanced melanoma, respectively. However, the majority of patients developed progressive disease.

This might be due to the fact that the numbers of administered ex vivo -activated autologous type I NKT cells were too low in comparison to the tumor load. Obtaining sufficient numbers of type I NKT cells might be a major challenge since type I NKT cell numbers are low in general, and especially in patients with cancer. Recently, studies focused on increasing the specificity of NKT cells by transducing them with chimeric antigen receptors that are not HLA or CD1d restricted 58 , 70 , Recently, Horn et al.

Another strategy that was suggested for the treatment of patients with solid tumors is vaccination with NKT-activating agents in combination with tumor antigens.

However, in our opinion, increasing the specificity of NKT cells is not the most promising method of increasing the effectiveness of NKT-based immunotherapies. The strength of NKT cells does not rest in their cytotoxic capacities, but in their regulatory function.

When the appropriate subsets are activated i. Therefore, instead of increasing the specificity of NKT cells, immunotherapies should focus on the most important function of NKT cells, their regulatory function. In conclusion, several NKT cell-based immunotherapies have been tested in clinical trials. To date, a beneficial effect in a minority of cancer patients has been reported.

We propose that it is essential to prevent and break NKT cell anergy in cancer patients and skew NKT cells in cancer patients toward T H 1-like subsets with antitumor activity in addition to expansion of the NKT cell population. In this review, we discussed the role of NKT cells in cancer and conclude that NKT cells play a central role in anticancer treatment due to their important regulatory function.

To improve NKT cell-based immunotherapies for the treatment of cancer patients, several aspects of the current treatment strategies need further attention. Combined with the fact that their numbers are decreased in cancer patients, it is essential to expand this cell population in patients. For instance, induced pluripotent stem cells might be used to expand the numbers of autologous NKT cells in patients ex vivo — Furthermore, culturing methods aiming at obtaining high numbers of NKT cells must be optimized.

At the moment, according to the Clinical Trials registry, multiple clinical trials 1 are ongoing that study the safety and clinical efficacy of adoptive type I NKT cell transfer in patients with solid tumors. As discussed in this review, this infusion should be accompanied by a protocol that prevents induction of NKT cell anergy and generation of immunosuppressive NKT cell subsets.

Until now, only a limited number of studies focused on prevention or breaking of NKT cell anergy. Parekh et al. In addition, in vitro and in vivo studies showed that stimulation of type I NKT cells with IL-2 overcomes anergy and restores their capacity to proliferate , NKT cells in which anergy was reversed retained their T H 2-biased cytokine profile upon IL-2 stimulation and did not change back toward a T H 1-like subset with antitumor activity It is therefore also necessary to use agents that are able to skew the cytokine profile of activated NKT cells toward a T H 1 profile, which means a change in functional subset.

In addition, Laurent et al. Hence, the use of modified NKT cell-activating agents in cancer patients might skew the cytokine profile of NKT cells toward a T H 1 profile while simultaneously preventing the induction of anergy. Due to their important regulatory function, NKT cells are promising candidates for immunotherapies in patients diagnosed with cancer.

However, NKT cell-based immunotherapies that focus on activating NKT cells have resulted in beneficial clinical responses in a minority of patients so far. In this review, we illustrated a hypothetical model regarding the role of NKT cells in solid tumors based on their function and phenotype.

During early tumor development, T H 1-like NKT cell subsets have the potential to initiate effective antitumor immune responses against tumors.

However, when NKT cells become overstimulated and anergic during tumor progression, they lose their antitumor function and start facilitating immune escape. The role of NKT cells in cancer might therefore be more dynamic than initially thought. So far, studies have primarily focused on methods to activate and expand the type I NKT cell population in patients, but the contribution of functionally altered NKT cells to the failure of NKT cell-based immunotherapies has been largely ignored.

In this review, we conclude that there should be three important focuses of future research in cancer patients: 1 expansion of the NKT cell population, 2 prevention and breaking of NKT cell anergy, and 3 skewing of NKT cells toward T H 1-like subsets with antitumor activity. DK compiled the literature sources, conceived of the presented idea, and wrote the manuscript.

PK and MH contributed to scientific discussions and critically reviewed the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Parkin J, Cohen B. An overview of the immune system. Lancet — Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells.

Stem Cell Res Ther 4 3 CD1d expression level in tumor cells is an important determinant for anti-tumor immunity by natural killer T cells. Leuk Lymphoma 47 10 — J Immunol 6 — Eur J Immunol 41 7 — The regulatory role of invariant NKT cells in tumor immunity.

Cancer Immunol Res 3 5 — Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 13 2 — NKT cell networks in the regulation of tumor immunity. Front Immunol Raising the NKT cell family. Nat Immunol 11 3 — Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria.

Nat Immunol 12 10 — Lysosomal glycosphingolipid recognition by NKT cells. Science —9. Kumar V, Delovitch TL. Different subsets of natural killer T cells may vary in their roles in health and disease. Immunology 3 — J Exp Med 1 :1— J Exp Med 6 — Research 16 April Open Access. Here, the authors generate a novel inducible MHC class-I trasnactivator murine system and suggest the absence of peptide-MHC on thymocytes is involved in the selection of non-peptide specific lymphocytes.

Research 07 December Open Access. Here the authors use single-cell RNA sequencing to show that mouse iNKT and MAIT share components of developmental regulation, with a transcription factor, Hivep3, implicated for the maturation of both cell types. Research 31 August Open Access.

Here, the authors show, using single-cell RNA sequencing, that all three cell types develop via shared and branched differentiation paths that are corroborated by additional results from gene-deficient mice and human liver T cells.

Research 27 July Verykokakis and colleagues show that the transcription factor BCL-6 is highly expressed in stage 0 NKT and is absolutely required for innate T cell lineage development. Reviews 24 June They focus on the cytokines, surface molecules and transcription factors that are necessary for the development of these cells and highlight some of the key differences from conventional T cell development.

Colonization of the mucosal tissues by iNKT cells was thought to be linked to the first contact with the environment. New research demonstrates that this process is regulated by and dependent on embryonic macrophages.