M2‑TAM subsets altered by lactic acid promote T‑cell apoptosis through the PD‑L1/PD‑1 pathway

Shan,Tao; Chen,Shuo; Chen,Xi; Wu,Tao; Yang,Yi; Li,Shunle; Ma,Jiancang; Zhao,Jing; Lin,Wanrun; Li,Wei; Cui,Xijuan; Kang,Ya'an

doi:10.3892/or.2020.7767

M2‑TAM subsets altered by lactic acid promote T‑cell apoptosis through the PD‑L1/PD‑1 pathway

Authors:
- Tao Shan
- Shuo Chen
- Xi Chen
- Tao Wu
- Yi Yang
- Shunle Li
- Jiancang Ma
- Jing Zhao
- Wanrun Lin
- Wei Li
- Xijuan Cui
- Ya'an Kang
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Affiliations: Department of General Surgery, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Chemistry, School of Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA, Department for Population and Development Studies, School of Public Policy and Administration, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of General Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Published online on: September 15, 2020 https://doi.org/10.3892/or.2020.7767
Pages: 1885-1894
Copyright: © Shan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the study was to investigate the effects of lactic acid on the phenotypic polarization and immune function of macrophages. The human monocyte/macrophage cell line, THP‑1, was selected and treated with lactic acid. Immunofluorescence staining, laser confocal microscopy, reverse‑transcription polymerase chain reaction (RT‑PCR), western blot, siRNA, and ELISA analyses were used to observe changes in the levels of cluster of differentiation (CD)68, CD163, hypoxia inducible factor (HIF)‑1α, and programmed death ligand‑1 (PD‑L1) as well as those of cytokines, tumor necrosis factor (TNF)‑α, interferon (IFN)‑γ, interleukin (IL)‑12, and IL‑10. THP‑1 macrophages and T cells were co‑cultured in vitro to observe the changes in proliferation and apoptosis of T cells. The results showed that, lactic acid (15 mmol/l) significantly upregulated the expression of the macrophage M2 marker CD163 (P<0.05), cytokines, IFN‑γ and IL‑10, secreted by M2‑tumor‑associated macrophages (TAM, P<0.05), and HIF‑1α and PD‑L1 (P<0.05), and downregulated the expression of cytokines, TNF‑α and IL‑12, secreted by M1‑TAM (P<0.05). Redistribution of M2‑TAM subsets and PD‑L1 expression was reversed after further transfection of THP‑1 cells with HIF‑1α siRNA (P<0.05). After co‑culturing, T‑cell proliferation was inhibited and apoptosis was promoted. In summary, modulation of lactic acid level can redistribute M2‑TAM subsets and upregulate PD‑L1 to assist tumor immune escape. The HIF‑1α signaling pathway may participate in this process, revealing that macrophages, as ‘checkpoints’ in organisms, are links that connect the immune status and tumor evolution, and can be used as a target in tumor treatment.

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