Loss of IFN-γ Production by Invariant NK T Cells in Advanced Cancer

Tahir, Syed Muhammad; Cheng, Olivia; Shaulov, Angela; Koezuka, Yasuhiko; Bubley, Glenn J.; Wilson, S. Brian; Balk, Steven P.; Exley, Mark A.

doi:10.4049/jimmunol.167.7.4046

Cited by 331 publications

(140 citation statements)

References 43 publications

(28 reference statements)

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“…It is also reported that the cytokine profile of NKT cells skews from IFN-γ dominant toward IL-4 dominant in advanced prostate cancer patients. The skewing of NKT cell cytokine profile toward IL-4 is associated with poor prognosis and decreased survival [39]. Herein, we examined if chronic alcohol consumption alters the cytokine profile of iNKT in the melanoma-bearing mice at the late stage of tumor growth.…”

Section: Resultsmentioning

confidence: 99%

“…It is reported that continuous activation induces iNKT cell anergy and that the anergic iNKT cells retain the function to produce IL-4 but are unable to produce IFN-γ [43, 44]. This phenomenon was also found in advanced prostate cancer patients [39]. We hypothesize that in the melanoma-bearing mice Signal I and Signal II continuously stimulate iNKT cells thus inducing iNKT cell anergy and that the Th2-dominant cytokine profile inhibits antitumor immunity and enhances tumor progression.…”

Section: Discussionmentioning

confidence: 99%

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Chronic alcohol consumption inhibits melanoma growth but decreases the survival of mice immunized with tumor cell lysate and boosted with α-galactosylceramide

Zhang

Zhu

Meadows

et al. 2015

International Immunopharmacology

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Alcohol consumption increases the incidence of multiple types of cancer. However, how chronic alcohol consumption affects tumor progression and host survival remains largely unexplored. Using a mouse B16BL6 melanoma model, we studied the effects of chronic alcohol consumption on s.c. tumor growth, iNKT cell antitumor immune response, and host survival. The results indicate that although chronic alcohol consumption inhibits melanoma growth, this does not translate into increased host survival. Immunizing mice with a melanoma cell lysate does not significantly increase the median survival of water-drinking, melanoma-bearing mice, but significantly increases the median survival of alcohol-consuming, melanoma-bearing mice. Even though survival is extended in the alcohol-consuming mice after immunization, the mean survival is not different from the immunized mice in the water-drinking group. Immunization with tumor cell lysate combined with α-galatosylceramide activation of iNKT cells significantly increases host survival of both groups of melanoma-bearing mice compared to their respective non-immunized counterparts; however, the median survival of the alcohol-consuming group is significantly lower than that of the water-drinking group. Alcohol consumption increases NKT cells in the thymus and blood and skews NKT cell cytokine profile from Th1 dominant to Th2 dominant in the tumor-bearing mice. In summary, these results indicate that chronic alcohol consumption activates the immune system, which leads to the inhibition of s.c. melanoma growth and enhances the immune response to immunization with melanoma lysate. With tumor progression, alcohol consumption accelerates iNKT cell dysfunction and compromises antitumor immunity, which leads to decreased survival of melanoma-bearing mice.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chronic alcohol consumption inhibits melanoma growth but decreases the survival of mice immunized with tumor cell lysate and boosted with α-galactosylceramide

Zhang

Zhu

Meadows

et al. 2015

International Immunopharmacology

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“…However, some of those patients with low IFNγ production showed no clinical effects (Motohashi et al, 2011). Additionally, decreased NKT cell numbers and impaired IFNγ productions have been reported previously in cancer patients and are related to poor clinical outcome (Molling et al, 2007;Motohashi et al, 2011;Muhammad Ali Tahir et al, 2001). Thus, optimal IFNγ production is important for the antitumor effects of NKT cells.…”

Section: Introductionmentioning

confidence: 92%

Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling

Xie

Zhu

Bai

2016

Sci. China Life Sci.

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Cellular metabolism has been shown to regulate differentiation and function of immune cells. Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments. NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials. However, the influences of tumor microenvironments on NKT cell functions remain unclear. In our studies, lactic acid in tumor microenvironments inhibited IFNγ and IL4 productions from NKT cells, and more profound influence on IFNγ was observed. By adjusting the pH of culture medium we further showed that, dysfunction of NKT cells could simply be induced by low extracellular pH. Moreover, low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin (mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger (PLZF). Together, our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.

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“…Recent clinical trials evaluating the effectiveness of NKT cell based immunotherapy in treating patients with solid tumors in the liver or lung, as well as unresectable head and neck cancers, have shown some promise (Ishikawa et al, 2005; Uchida et al, 2008). Collectively, these studies and others (Kawano et al, 1999b; Tahir et al, 2001; Fujii et al, 2003a) have demonstrated that many cancer patients have a deficiency in both NKT cell number and function, which suggests that in vivo NKT cell modulation would only be effective in patients with sufficient numbers of functional NKT cells.…”

Section: Introductionmentioning

confidence: 80%

Development of a qPCR method to rapidly assess the function of NKT cells

Sohn

Tiper

Japp

et al. 2014

Journal of Immunological Methods

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NKT cells comprise a rare, but important subset of T cells which account for ~0.2% of the total circulating T cell population. NKT cells are known to have anti-tumor functions and rapidly produce high levels of cytokines following activation. Several clinical trials have sought to exploit the effector functions of NKT cells. While some studies have shown promise, NKT cells are approximately 50% lower in cancer patients compared to healthy donors of the same age and gender, thus limiting their therapeutic efficacy. These studies indicate that baseline levels of activation should be assessed before initiating an NKT cell based immunotherapeutic strategy, thus the goal of this study was to develop a sensitive method to rapidly assess NKT cell function. We utilized artificial antigen presenting cells in combination with qPCR in order to determine NKT cell function in peripheral blood mononuclear cells from healthy donors and breast cancer patients. We found that NKT cell activation can be detected by qPCR, but not by ELISA, in healthy donors as well as in breast cancer patients following four hour stimulation. This method utilizing CD1d-expressing aAPC will enhance our knowledge of NKT cell biology and could potentially be used as a novel tool in adoptive immunotherapeutic strategies.

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Loss of IFN-γ Production by Invariant NK T Cells in Advanced Cancer

Cited by 331 publications

References 43 publications

Chronic alcohol consumption inhibits melanoma growth but decreases the survival of mice immunized with tumor cell lysate and boosted with α-galactosylceramide

Chronic alcohol consumption inhibits melanoma growth but decreases the survival of mice immunized with tumor cell lysate and boosted with α-galactosylceramide

Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling

Development of a qPCR method to rapidly assess the function of NKT cells

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