Dataset Information

Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells.

ABSTRACT:

Introduction

Lactate secreted by tumors is not just a byproduct, but rather an active modulator of immune cells. There are few studies aimed at investigating the true effect of lactate, which is normally confounded by pH. Such a knowledge gap needs to be addressed. Herein, we studied the immunomodulatory effects of lactate on dendritic cells (DCs) and macrophages (MΦs).

Methods

Bone marrow-derived innate immune cells were treated with 50 mM sodium lactate (sLA) and incubated for 2 days or 5 days at 37 °C. Controls included media, lipopolysaccharide (LPS), MCT inhibitors (α-cyano-4-hydroxycinnamic acid and AR-C15585). Flow cytometric analysis of immune phenotypes were performed by incubating cells with specific marker antibodies and viability dye. Differential expression analyses were conducted on R using limma-voom and adjusted p-values were generated using the Bejamini-Hochberg Procedure.

Results

Lactate exposure attenuated DC maturation through the downregulation of CD80 and MHCII expression under LPS stimulation. For MΦs, lactate exposure resulted in M2 polarization as evidenced by the reduction of M1 markers (CD38 and iNOS), and the increase in expression of CD163 and Arg1. We also revealed the role of monocarboxylate transporters (MCTs) in mediating lactate effect in MΦs. MCT4 inhibition significantly boosted lactate M2 polarization, while blocking of MCT1/2 failed to reverse the immunosuppressive effect of lactate, correlating with the result of gene expression that lactate increased MCT4 expression, but downregulated the expression of MCT1/2.

Conclusions

This research provides valuable insight on the influence of metabolic products on tumor immunity and will help to identify novel metabolic targets for augmenting cancer immunotherapies.

SUBMITTER: Sangsuwan R

PROVIDER: S-EPMC7596145 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells.

Sangsuwan Rapeepat R Thuamsang Bhasirie B Pacifici Noah N Allen Riley R Han Hyunsoo H Miakicheva Svetlana S Lewis Jamal S JS

Cellular and molecular bioengineering 20200921 5

<h4>Introduction</h4>Lactate secreted by tumors is not just a byproduct, but rather an active modulator of immune cells. There are few studies aimed at investigating the true effect of lactate, which is normally confounded by pH. Such a knowledge gap needs to be addressed. Herein, we studied the immunomodulatory effects of lactate on dendritic cells (DCs) and macrophages (MΦs).<h4>Methods</h4>Bone marrow-derived innate immune cells were treated with 50 mM sodium lactate (sLA) and incubated for 2 ...[more]

PMID: 33184582

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Project description:BackgroundThe metabolic reprogramming of mesenchymal stem/stromal cells (MSC) favoring glycolysis has recently emerged as a new approach to improve their immunotherapeutic abilities. This strategy is associated with greater lactate release, and interestingly, recent studies have proposed lactate as a functional suppressive molecule, changing the old paradigm of lactate as a waste product. Therefore, we evaluated the role of lactate as an alternative mediator of MSC immunosuppressive properties and its contribution to the enhanced immunoregulatory activity of glycolytic MSCs.Materials and methodsMurine CD4+ T cells from C57BL/6 male mice were differentiated into proinflammatory Th1 or Th17 cells and cultured with either L-lactate, MSCs pretreated or not with the glycolytic inductor, oligomycin, and MSCs pretreated or not with a chemical inhibitor of lactate dehydrogenase A (LDHA), galloflavin or LDH siRNA to prevent lactate production. Additionally, we validated our results using human umbilical cord-derived MSCs (UC-MSCs) in a murine model of delayed type 1 hypersensitivity (DTH).ResultsOur results showed that 50 mM of exogenous L-lactate inhibited the proliferation rate and phenotype of CD4+ T cell-derived Th1 or Th17 by 40% and 60%, respectively. Moreover, the suppressive activity of both glycolytic and basal MSCs was impaired when LDH activity was reduced. Likewise, in the DTH inflammation model, lactate production was required for MSC anti-inflammatory activity. This lactate dependent-immunosuppressive mechanism was confirmed in UC-MSCs through the inhibition of LDH, which significantly decreased their capacity to control proliferation of activated CD4+ and CD8+ human T cells by 30%.ConclusionThese findings identify a new MSC immunosuppressive pathway that is independent of the classical suppressive mechanism and demonstrated that the enhanced suppressive and therapeutic abilities of glycolytic MSCs depend at least in part on lactate production.

Dataset Information

Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells.

Introduction

Methods

Results

Conclusions

Publications

Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells.

Similar Datasets

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