Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells
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Cellular and Molecular Bioengineering ( 2020) https://doi.org/10.1007/s12195-020-00652-x
2020 CMBE Young Innovators issue
Lactate Exposure Promotes Immunosuppressive Phenotypes in Innate Immune Cells RAPEEPAT SANGSUWAN, BHASIRIE THUAMSANG, NOAH PACIFICI, RILEY ALLEN, HYUNSOO HAN, SVETLANA MIAKICHEVA, and JAMAL S. LEWIS Department of Biomedical Engineering, University of California, Davis, 1 Shields Avenue, Davis, CA 95616, USA (Received 2 March 2020; accepted 8 September 2020) Associate Editor Shelly Peyton oversaw the review of this article.
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 (MFs). 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 (a-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 pvalues 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 MFs, 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 MFs. 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. Keywords—Lactate, Dendritic cells, Macrophages, Immune escape, Cancer, Immunosuppressive.
Address correspondence to Jamal S. Lewis, Department of Biomedical Engineering, University of California, Davis, 1 Shields Avenue, Davis, CA 95616, USA. Electronic mail: jamlewis@ ucdavis.edu
INTRODUCTION The field of cancer immunotherapy has recently been invigorated with the successful clinical trials of several cell-based approaches, including CAR T cell immunotherapy. Despite these improved outcomes in clinical trials showing response rates greater than 50% for liquid tumors, successful application of these approaches to solid tumors has been rare in the clinic.3,33 The tumor microenvironment (TME) of solid tumors has been directly imp
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