CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: α-Galactosylceramide and Beyond

King, Lisa A.; Lameris, Roeland; Gruijl, Tanja D. de; Vliet, Hans J. van der

doi:10.3389/fimmu.2018.01519

Cited by 27 publications

(31 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11,12 In most clinical studies DCs or PBMCs were loaded with α-GalCer ex-vivo before being administered into patients. 13 It was reported that intravenously (iv) injected cells led to a higher increase of iNKT cell numbers than intradermally (id) administered cells and the iv injected cells were only able to induce IFN-y production by T and NK cells. 14 However, in this study, id injected moDCs were unable to migrate to peripheral lymph nodes invalidating the comparison.…”

Section: Introductionmentioning

confidence: 99%

Nanovaccine administration route is critical to obtain pertinent iNKt cell help for robust anti-tumor T and B cell responses

et al. 2020

View full text Add to dashboard Cite

Nanovaccines, co-delivering antigen and invariant natural killer T (iNKT) cell agonists, proved to be very effective in inducing anti-tumor T cell responses due to their exceptional helper function. However, it is known that iNKT cells are not equally present in all lymphoid organs and nanoparticles do not get evenly distributed to all immune compartments. In this study, we evaluated the effect of the vaccination route on iNKT cell help to T and B cell responses for the first time in an antigen and agonist co-delivery setting. Intravenous administration of PLGA nanoparticles was mainly targeting liver and spleen where iNKT1 cells are abundant and induced the highest serum IFN-y levels, T cell cytotoxicity, and Th-1 type antibody responses. In comparison, after subcutaneous or intranodal injections, nanoparticles mostly drained or remained in regional lymph nodes where iNKT17 cells were abundant. After subcutaneous and intranodal injections, antigen-specific IgG2 c production was hampered and IFN-y production, as well as cytotoxic T cell responses, depended on sporadic systemic drainage. Therapeutic anti-tumor experiments also demonstrated a clear advantage of intravenous injection over intranodal or subcutaneous vaccinations. Moreover, tumor control could be further improved by PD-1 immune checkpoint blockade after intravenous vaccination, but not by intranodal vaccination. Anti PD-1 antibody combination mainly exerts its effect by prolonging the cytotoxicity of T cells. Nanovaccines also demonstrated synergism with anti-4-1BB agonistic antibody treatment in controlling tumor growth. We conclude that nanovaccines containing iNKT cell agonists shall be preferentially administered intravenously, to optimally reach cellular partners for inducing effective anti-tumor immune responses.

show abstract

Section: Introductionmentioning

confidence: 99%

Nanovaccine administration route is critical to obtain pertinent iNKt cell help for robust anti-tumor T and B cell responses

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Thus far, clinical studies have mainly focused on adoptive transfer of autologous iNKT cell enriched in vitro- expanded populations from peripheral blood mononuclear cells (PBMCs), αGalCer-pulsed monocyte-derived DCs or a combination of activated iNKT and αGalCer pulsed DCs ( 95 – 99 ). Also administration of soluble αGalCer has been tested in clinical trials ( 98 , 99 ). Currently, clinical benefits are still relatively limited and combinations as well as optimized strategies are being considered ( 96 , 99 ).…”

Section: Innate Lymphocyte Subsets In Natural and Therapeutic Anti-tumentioning

confidence: 99%

“…Also administration of soluble αGalCer has been tested in clinical trials ( 98 , 99 ). Currently, clinical benefits are still relatively limited and combinations as well as optimized strategies are being considered ( 96 , 99 ). Since ex vivo expansion of circulating iNKT has to overcome their low frequencies in blood, induced pluripotent stem cells (iPSCs) for the generation of large numbers of iNKT might provide an alternative ( 100 ).…”

Section: Innate Lymphocyte Subsets In Natural and Therapeutic Anti-tumentioning

confidence: 99%

“…On the other hand, non-invariant/diverse NKT subsets (“Type II NKT”) can actively downregulate tumor immunity through different mechanisms ( 91 – 94 ). In the future, a more complete and evolving understanding of reversible type I NKT defects together with more insight in the mechanism behind type II NKT cell mediated suppression of antitumor immune responses (or other activities of these less understood and more diverse populations), should help the development and evaluation of novel and successful cancer therapies involving NKT populations ( 99 , 103 ).…”

Section: Innate Lymphocyte Subsets In Natural and Therapeutic Anti-tumentioning

confidence: 99%

See 1 more Smart Citation

Positive & Negative Roles of Innate Effector Cells in Controlling Cancer Progression

et al. 2018

Self Cite

View full text Add to dashboard Cite

Innate immune cells are active at the front line of host defense against pathogens and now appear to play a range of roles under non-infectious conditions as well, most notably in cancer. Establishing the balance of innate immune responses is critical for the “flavor” of these responses and subsequent adaptive immunity and can be either “good or bad” in controlling cancer progression. The importance of innate NK cells in tumor immune responses has already been extensively studied over the last few decades, but more recently several relatively mono- or oligo-clonal [i.e., (semi-) invariant] innate T cell subsets received substantial interest in tumor immunology including invariant natural killer T (iNKT), γδ-T and mucosal associated invariant T (MAIT) cells. These subsets produce high levels of various pro- and/or anti-inflammatory cytokines/chemokines reflecting their capacity to suppress or stimulate immune responses. Survival of patients with cancer has been linked to the frequencies and activation status of NK, iNKT, and γδ-T cells. It has become clear that NK, iNKT, γδ-T as well as MAIT cells all have physiological roles in anti-tumor responses, which emphasize their possible relevance for tumor immunotherapy. A variety of clinical trials has focused on manipulating NK, iNKT, and γδ-T cell functions as a cancer immunotherapeutic approach demonstrating their safety and potential for achieving beneficial therapeutic effects, while the exploration of MAIT cell related therapies is still in its infancy. Current issues limiting the full therapeutic potential of these innate cell subsets appear to be related to defects and suppressive properties of these subsets that, with the right stimulus, might be reversed. In general, how innate lymphocytes are activated appears to control their subsequent abilities and consequent impact on adaptive immunity. Controlling these potent regulators and mediators of the immune system should enable their protective roles to dominate and their deleterious potential (in the specific context of cancer) to be mitigated.

show abstract

“…We assess ILT cells within PBMC samples in this study, since previous studies have demonstrated ILT cell phenotypes in PBMC to be comparable with AT (14). As important first step toward therapeutic application, we also provide a differentiating analysis of MAIT, iNKT, and Vδ2 + T cell cytokine secretion upon general activation (i.e., combination of phorbol myristate acetate (PMA) and ionomycin) as well as stimulation using the MAIT agonist precursor 5-amino-6-D-ribitylaminouracil [5-A-RU (24)], and the iNKT and Vγ9 + Vδ2 + T cell agonists α-galactosylceramide [α-GC; used clinically by us and others (21,25)] and 4-bromo-3hydroxy-3-methylbutyl diphosphate [BrHPP; the only clinically tested phosphoantigen (26,27)], respectively.…”

Section: Introductionmentioning

confidence: 99%

Distinct Dysfunctional States of Circulating Innate-Like T Cells in Metabolic Disease

Woods

Parry‐Strong

et al. 2020

Front. Immunol.

View full text Add to dashboard Cite

The immune system plays a significant role in controlling systemic metabolism. Innate-like T (ILT) cells in particular, such as mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells and γδ T cell receptor expressing cells, have been reported to promote metabolic homeostasis. However, these different ILT cell subsets have, to date, been generally studied in isolation. Here we conducted a pilot study assessing the phenotype and function of circulating MAIT, iNKT, and Vδ2 + T cells in a small cohort of 10 people with obesity and type 2 diabetes (T2D), 10 people with obesity but no diabetes, and 12 healthy individuals. We conducted phenotypic analysis by flow cytometry ex vivo, and then functional analysis after in vitro stimulation using either PMA/ionomycin or synthetic agonists, or precursors thereof, for each of the cell-types; use of the latter may provide important knowledge for the development of novel therapeutics aimed at activating human ILT cells. The results of our pilot study, conducted on circulating cells, show clear dysfunction of all three ILT cell subsets in obese and obese T2D patients, as compared to healthy controls. Importantly, while both iNKT and Vδ2 + T cell dysfunctions were characterized by diminished IL-2 and interferon-γ production, the distinct dysfunctional state of MAIT cells was instead defined by skewed subset composition, heightened sensitivity to T cell receptor engagement and unchanged production of all measured cytokines.

show abstract

CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: α-Galactosylceramide and Beyond

Cited by 27 publications

References 61 publications

Nanovaccine administration route is critical to obtain pertinent iNKt cell help for robust anti-tumor T and B cell responses

Nanovaccine administration route is critical to obtain pertinent iNKt cell help for robust anti-tumor T and B cell responses

Positive & Negative Roles of Innate Effector Cells in Controlling Cancer Progression

Distinct Dysfunctional States of Circulating Innate-Like T Cells in Metabolic Disease

Contact Info

Product

Resources

About