Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity

O’Konek, Jessica J.; Illarionov, Petr A.; Khursigara, Deborah Stewart; Ambrosino, Elena; Izhak, Liat; Castillo, Bernard F.; Raju, Ravinder; Khalili, Maryam; Kim, Hee Yong; Howell, Amy R.; Besra, Gurdyal S.; Porcelli, Steven A.; Berzofsky, Jay A.; Terabe, Masaki

doi:10.1172/jci42314

Cited by 41 publications

(63 citation statements)

References 66 publications

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“…A recent study by O'Konek et al reported similar findings that, through NKT cell activation, ␤-ManCer injection was capable of inducing equivalent antitumor activities to ␣-GalCer against experimental lung metastases of B16F10 melanoma and CT26 colon carcinoma, in a NOS-and TNF-␣-dependent manner. 32 This was despite no substantial increases in cytokine production in vivo after treatment, including undetectable IFN-␥ and TNF-␣. In agreement with these findings, we could not detect IFN-␥, IL-12, or TNF-␣ 24 hours after vaccination with ␤-ManCer-loaded tumors, although it is possible that ␤-ManCer elicits different kinetics of immune cell activation and cytokine production, as previously reported for other glycolipids.…”

Section: Discussionmentioning

confidence: 99%

“…32,33 To determine whether alternative glycolipids loaded onto E-myc tumor cells gave superior protection against E-myc lymphoma, WT C57BL/6 mice with established lymphoma received irradiated E-myc tumor cells loaded with either the C-glycoside analog of ␣-GalCer (␣-C-GalCer), OCH or ␤-ManCer. Other than OCH, each of these glycolipids loaded onto tumor vaccine suppressed E-myc tumor growth in the first 12 days after vaccination to similar levels as ␣-GalCer ( Figure 7A).…”

Section: Irradiated E-myc Tumors Loaded With ␤-Mancer Causes Prolongementioning

confidence: 99%

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NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma

Mattarollo

West

Steegh

et al. 2012

Blood

121

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Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating ␣-galactosylceramide IntroductionHematologic malignancies typically express the necessary machinery for eliciting antitumor immunity, such as costimulatory molecules, yet many tumors are poorly immunogenic. Therapeutic vaccination strategies that incorporate immune adjuvants are likely to enhance immune recognition and targeting of hematologic cancers, an example being in mice vaccinated against mouse lymphomas with whole tumor cells loaded with CpG adjuvant. 1 Natural killer T (NKT) lymphocytes represent an immune regulatory population with recognized capacity for inducing innate (eg, NK cells) and adaptive (eg, CD8 T cell) antitumor immunity, [2][3][4] by their unique ability to rapidly produce large quantities of cytokines on TCR ligation, in particular IFN-␥. 5,6 As a result, the synthetic CD1d-dependent NKT cell ligand ␣-galactosylceramide (␣-GalCer) has been used for its NKT cell-mediated immune adjuvant properties in anticancer therapies. [7][8][9][10] Initial attempts to stimulate NKT cells in situ were to simply infuse soluble ␣-GalCer, which briefly inhibited the tumor growth, but had limited effects on survival. 11,12 In addition, multiple injections of ␣-GalCer led to deleterious effects including long-term NKT cell functional anergy or unresponsiveness. 12 Subsequently, ␣-GalCer was loaded onto dendritic cells (DCs) as a vaccine. This approach induced more potent antitumor effects than soluble ␣-GalCer injections, mainly by prolonging NKT cell IFN-␥ production and preventing induction of NKT cell anergy, and was able to significantly improve the activity of the DC vaccine if coadministered with tumor antigens. 10,13,14 The cumbersome nature of inducing and expanding DC from patients' peripheral blood monocytes for autologous ␣-GalCerpulsed DC therapy stimulated the use of irradiated tumor cells as a vehicle to deliver ␣-GalCer in vivo. [15][16][17] Here a full complement of tumor antigens (including undefined ones) and ␣-GalCer are codelivered, thus allowing generation of innate immunity and potentially long-term tumor-specific T-cell adaptive immunity. In a prophylactic setting, whole tumor cells loaded with ␣-GalCer were able to protect mice against subsequent challenge with live tumor cells 15,16 and were also shown to be partially effective at inhibiting growth of established solid tumors 17 (S.R.M., K.S., M. Li, H.D., S.F. Ngiow, M.J.S., Transient Foxp3 ϩ regulatory T cell depletion enhances therapeutic anticancer vaccination targeting the immunestimulatory properties of NKT cells, manuscript submitted, August 2012), demonstrating the ability of this vaccine to work successfully in a The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by ...

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Section: Discussionmentioning

confidence: 99%

Section: Irradiated E-myc Tumors Loaded With ␤-Mancer Causes Prolongementioning

confidence: 99%

NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma

Mattarollo

West

Steegh

et al. 2012

Blood

121

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“…Since TAMs provide a critical stromal support for tumor cell growth in NB and many other types of cancer (13)(14)(15), NKT cell-mediated killing or inhibition of TAMs explains how NKT cells may indirectly impede tumor growth. Other recent reports have generated additional evidence for the importance of NKT cell interactions with monocytic cells and other myeloid cells in viral and tumor immunity (16,17) and in the potential mechanism of antitumor activity of the NKT cell ligand β-manosylceramide (18).…”

Section: Introductionmentioning

confidence: 98%

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

et al. 2012

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“…Interestingly, the recently described novel agonist of human and murine iNKTs, β-mannosylceramide, confers protection against tumors via a different mechanism involving production of nitric oxide and tumor necrosis factor-α. 32 Recent studies also show that iNKTs protect against B-cell lymphomas in mice 33 and that infection of humanized mice with EBV promotes the generation of cytotoxic iNKTs, which produce IFN-γ and enhance T-cell killing of EBV-positive human tumor cells. 34 Finally, generation of induced pluripotent stem cells (iPSCs) from mature iNKTs can activate and expand Ag-specific CD8 + T cell responses to provide protection against leukemia in mice.…”

Section: Inkts and Antitumor Immunity Inkts Protect Against Tumorsmentioning

confidence: 99%

“…97 Interestingly, in a recent study low doses of αGC and β-mannosylceramide acted synergistically to modulate iNKT responses in a preclinical tumor model. 32 Whether this strategy can suppress GvHD, remains to be determined. Previously, it was shown that lenalidomide, a thalidomide analog enhances αGC-induced iNKT expansion and IFN-γ production in both healthy donors and patients with MM, 98 suggesting that combining iNKT ligands with lenalidomide may provide a viable approach to enhance the efficacy of either therapy against human cancer.…”

Section: Human Cd4mentioning

confidence: 99%

Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression

Guan

Bassiri

Patel

et al. 2016

Bone Marrow Transplant

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Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity

Cited by 41 publications

References 66 publications

NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma

NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression

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