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Platelets subvert T cell immunity against cancer via GARP-TGF? axis.

ABSTRACT: Cancer-associated thrombocytosis has long been linked to poor clinical outcome, but the underlying mechanism is enigmatic. We hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. We show that genetic targeting of platelets enhances adoptive T cell therapy of cancer. An unbiased biochemical and structural biology approach established transforming growth factor ? (TGF?) and lactate as major platelet-derived soluble factors to obliterate CD4+ and CD8+ T cell functions. Moreover, we found that platelets are the dominant source of functional TGF? systemically as well as in the tumor microenvironment through constitutive expression of the TGF?-docking receptor glycoprotein A repetitions predominant (GARP) rather than secretion of TGF? per se. Platelet-specific deletion of the GARP-encoding gene Lrrc32 blunted TGF? activity at the tumor site and potentiated protective immunity against both melanoma and colon cancer. Last, this study shows that T cell therapy of cancer can be substantially improved by concurrent treatment with readily available antiplatelet agents. We conclude that platelets constrain T cell immunity through a GARP-TGF? axis and suggest a combination of immunotherapy and platelet inhibitors as a therapeutic strategy against cancer.

SUBMITTER: Rachidi S

PROVIDER: S-EPMC5539882 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Platelets subvert T cell immunity against cancer via GARP-TGFβ axis.

Rachidi Saleh S Metelli Alessandra A Riesenberg Brian B Wu Bill X BX Nelson Michelle H MH Wallace Caroline C Paulos Chrystal M CM Rubinstein Mark P MP Garrett-Mayer Elizabeth E Hennig Mirko M Bearden Daniel W DW Yang Yi Y Liu Bei B Li Zihai Z

Science immunology 20170501 11

Cancer-associated thrombocytosis has long been linked to poor clinical outcome, but the underlying mechanism is enigmatic. We hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. We show that genetic targeting of platelets enhances adoptive T cell therapy of cancer. An unbiased biochemical and structural biology approach established transforming growth factor β (TGFβ) and lactate as major platelet-derived soluble factors to obliterate CD4<sup>+</su ...[more]

PMID: 28763790

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Project description:BACKGROUND:Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson's disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS:Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS:We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS:These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

Dataset Information

Platelets subvert T cell immunity against cancer via GARP-TGF? axis.

Publications

Platelets subvert T cell immunity against cancer via GARP-TGFβ axis.

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