Augmentation of murine natural killer cell activity by manganese chloride

Rogers, Ronald R.; Garner, R. J.; Riddle, Marie M.; Luebke, Robert W.; Smialowicz, Ralph J.

doi:10.1016/0041-008x(83)90174-6

Cited by 28 publications

(5 citation statements)

References 29 publications

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“…So we next tested the effect of Mn 2+ on NK cells isolated from mouse spleens. Consistent with previous reports demonstrating that Mn 2+ enhanced NK cell activation, 48 , 49 NK cells were highly activated by Mn 2+ treatment in vitro, as the expression of CD107a and granzyme B was significantly enhanced (Supplementary information, Fig. S3i ).…”

Section: Resultssupporting

confidence: 92%

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

et al. 2020

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CD8+ T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8+ T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8+ T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8+ T cells. Mechanically, Mn2+ promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8+ T cell differentiation, activation and NK cell activation, and increased memory CD8+ T cells. Combining Mn2+ with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn2+ and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.

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Section: Resultssupporting

confidence: 92%

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

et al. 2020

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“…The role of dietary manganese and susceptibility to infectious disease is not well described, though a role for manganese in immune function has been implicated. For instance, manganese excess increases expression of pro-inflammatory cytokines from neuron-associated glial cells (Dodd and Filipov, 2011) and macrophages (Mokgobu et al, 2015) as well as enhances natural killer cell (Rogers et al, 1983) and macrophage activity (Smialowicz et al, 1985). However, high manganese also inhibits lymphocyte proliferation (Hart, 1978), exemplifying how balancing metal levels is necessary for optimum immune function.…”

Section: Dietary Metals At the Host-pathogen Interface Of Extraintestmentioning

confidence: 99%

The Impact of Dietary Transition Metals on Host-Bacterial Interactions

Lopez

Skaar

2018

Cell Host & Microbe

151

140

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Transition metals are required cofactors for many proteins that are critical for life, and their concentration within cells is carefully maintained to avoid both deficiency and toxicity. To defend against bacterial pathogens, vertebrate immune proteins sequester metals, in particular zinc, iron, and manganese, as a strategy to limit bacterial acquisition of these necessary nutrients in a process termed "nutritional immunity." In response, bacteria have evolved elegant strategies to access metals and counteract this host defense. In mammals, metal abundance can drastically shift due to changes in dietary intake or absorption from the intestinal tract, disrupting the balance between host and pathogen in the fight for metals and altering susceptibility to disease. This review describes the current understanding of how dietary metals modulate host-microbe interactions and the subsequent impact on the outcome of disease.

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“…As a consequence, both dendritic cells and macrophage maturation contribute to CD8 + T-cell activation and better tumour control in a B16 melanoma model. Congruently, as first reported in the 1980s, Mn 2+ supplementation leads to a significant increase in the number of TILs [41][42][43]. In addition, Mn 2+ treatment increases cytokine production capacity in both CD8 + T and NK infiltrating tumours, while depletion of Mn 2+ from the diet results in a reduced T cells differentiation and increased tumour size.…”

Section: Manganesementioning

confidence: 69%

Ionic Regulation of T-Cell Function and Anti-Tumour Immunity

Ginefra

Hope

Spagna

et al. 2021

IJMS

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The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism.

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Augmentation of murine natural killer cell activity by manganese chloride

Cited by 28 publications

References 29 publications

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

The Impact of Dietary Transition Metals on Host-Bacterial Interactions

Ionic Regulation of T-Cell Function and Anti-Tumour Immunity

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