Type I natural killer T cells suppress tumors caused by p53 loss in mice

Swann, Jeremy B.; Uldrich, Adam P.; Dommelen, Serani van; Sharkey, Janelle; Murray, William K.; Godfrey, Dale I.; Smyth, Mark J.

doi:10.1182/blood-2009-01-198564

Cited by 100 publications

(64 citation statements)

References 26 publications

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“…Whereas decreases in NKT cell number and/or function have been linked to increased tumor incidence and progression, 8,9,41 NKT cell activation has been shown to enhance antitumor responses. 7,15,16,21,30,31 Although clinical trials examining NKT cell activation therapies in patients with advanced/recurrent disease have reported few cases of objective tumor regression, tumors tended to remain stable without the appearance of new metastatic foci.…”

Section: Discussionmentioning

confidence: 99%

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Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

et al. 2015

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Metastatic lesions are responsible for over 90% of breast cancer associated deaths. Therefore, strategies that target metastasis are of particular interest. This study examined the efficacy of natural killer T (NKT) cell activation as a postsurgical immunotherapy in a mouse model of metastatic breast cancer. Following surgical resection of orthotopic 4T1 mammary carcinoma tumors, BALB/c mice were treated with NKT cell activating glycolipid antigens (a-GalCer, a-CGalCer or OCH) or a-GalCer-loaded dendritic cells (DCs). Low doses of glycolipids transiently reduced metastasis but did not increase survival. A high dose of a-GalCer enhanced overall survival, but was associated with increased toxicity and mortality at early time points. Treatment with a-GalCer-loaded DCs limited tumor metastasis, prolonged survival, and provided curative outcomes in »45% of mice. However, survival was not increased further by additional DC treatments or co-transfer of expanded NKT cells. NKT cell activation via glycolipid-loaded DCs decreased the frequency and immunosuppressive activity of myeloid derived suppressor cells (MDSCs) in tumor-resected mice. In vitro, NKT cells were resistant to the immunosuppressive effects of MDSCs and were able to reverse the inhibitory effects of MDSCs on T cell proliferation. NKT cell activation enhanced antitumor immunity in tumor-resected mice, increasing 4T1-specific cytotoxic responses and IFNg production from natural killer (NK) cells and CD8 C T cells. Consistent with increased tumor immunity, mice surviving to day 150 were resistant to a second tumor challenge. This work provides a clear rationale for manipulating NKT cells to target metastatic disease.

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Section: Discussionmentioning

confidence: 99%

“…8,9 This is likely mediated by recognition of tumor-associated glycolipid antigens, 10 stress induced glycolipid self-antigens, 11,12 or inflammatory cytokines. 13,14 Preclinical and clinical studies have shown that NKT cell activation with exogenous glycolipids provides significant protection from tumor progression.…”

Section: Introductionmentioning

confidence: 99%

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

et al. 2015

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“…Natural killer T cells are a unique population of T cells involved in the regulation of autoimmunity, infection, immune tolerance and tumor immunosurveillance (Godfrey and Kronenberg, 2004;Swann et al, 2009). NKT cells recognize glycolipids presented in the context of the major histocompatibility complex class I-like molecule CD1d and produce large amounts of cytokines upon activation.…”

Section: Adenosine-mediated Immunosuppressionmentioning

confidence: 99%

Extracellular adenosine triphosphate and adenosine in cancer

2010

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Adenosine triphosphate (ATP) is actively released in the extracellular environment in response to tissue damage and cellular stress. Through the activation of P2X and P2Y receptors, extracellular ATP enhances tissue repair, promotes the recruitment of immune phagocytes and dendritic cells, and acts as a co-activator of NLR family, pyrin domain-containing 3 (NLRP3) inflammasomes. The conversion of extracellular ATP to adenosine, in contrast, essentially through the enzymatic activity of the ecto-nucleotidases CD39 and CD73, acts as a negativefeedback mechanism to prevent excessive immune responses. Here we review the effects of extracellular ATP and adenosine on tumorigenesis. First, we summarize the functions of extracellular ATP and adenosine in the context of tumor immunity. Second, we present an overview of the immunosuppressive and pro-angiogenic effects of extracellular adenosine. Third, we present experimental evidence that extracellular ATP and adenosine receptors are expressed by tumor cells and enhance tumor growth. Finally, we discuss recent studies, including our own work, which suggest that therapeutic approaches that promote ATP-mediated activation of inflammasomes, or inhibit the accumulation of tumorderived extracellular adenosine, may constitute effective new means to induce anticancer activity.

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“…As a consequence of these helper functions, iNKT cells are implicated in the control of infections and cancer. Evidence in mouse models and in cancer patients indeed suggests an active role of iNKT cells in the immune surveillance of different solid tumors, lymphoma, and multiple myeloma (25)(26)(27). Whether iNKT cell might also play a role in controlling other relevant hematological malignancies, such as leukemia, is not known.…”

mentioning

confidence: 99%

Invariant NKT Cell Reconstitution in Pediatric Leukemia Patients Given HLA-Haploidentical Stem Cell Transplantation Defines Distinct CD4+ and CD4− Subset Dynamics and Correlates with Remission State

Lalla

Rinaldi

Montagna

et al. 2011

The Journal of Immunology

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Immune reconstitution plays a crucial role on the outcome of patients given T cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (hHSCT) for hematological malignancies. CD1d-restricted invariant NKT (iNKT) cells are innate-like, lipid-reactive T lymphocytes controlling infections, cancer, and autoimmunity. Adult mature iNKT cells are divided in two functionally distinct CD4+ and CD4− subsets that express the NK receptor CD161 and derive from thymic CD4+CD161− precursors. We investigated iNKT cell reconstitution dynamics in 33 pediatric patients given hHSCT for hematological malignancies, with a follow-up reaching 6 y posttransplantation, and correlated their emergence with disease relapse. iNKT cells fully reconstitute and rapidly convert into IFN-γ–expressing effectors in the 25 patients maintaining remission. CD4+ cells emerge earlier than the CD4− ones, both displaying CD161− immature phenotypes. CD4− cells expand more slowly than CD4+ cells, though they mature with significantly faster kinetics, reaching full maturation by 18 mo post-hHSCT. Between 4 and 6 y post-hHSCT, mature CD4− iNKT cells undergo a substantial expansion burst, resulting in a CD4+<CD4− NKT cell ratio similar to that found in healthy adults. In contrast with patients maintaining remission, iNKT cells failed to reconstitute in all eight patients experiencing disease relapse. These findings define the peripheral dynamics of human iNKT cells and suggest a contribution of these cells to maintain remission, possibly via early IFN-γ provision. Adoptive transfer of donor-derived iNKT cells into HLA-haploidentical patients failing to reconstitute these cells might represent a novel therapeutic option to prevent leukemia recurrence.

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Type I natural killer T cells suppress tumors caused by p53 loss in mice

Cited by 100 publications

References 26 publications

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Extracellular adenosine triphosphate and adenosine in cancer

Invariant NKT Cell Reconstitution in Pediatric Leukemia Patients Given HLA-Haploidentical Stem Cell Transplantation Defines Distinct CD4+ and CD4− Subset Dynamics and Correlates with Remission State

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