TY - JOUR
T1 - M2-TAM subsets altered by lactic acid promote T-cell apoptosis through the PD-L1/PD-1 pathway
AU - SHAN, TAO
AU - CHEN, SHUO
AU - CHEN, XI
AU - WU, TAO
AU - YANG, YI
AU - LI, SHUNLE
AU - MA, JIANCANG
AU - ZHAO, JING
AU - LIN, WANRUN
AU - LI, WEI
AU - CUI, XIJUAN
AU - KANG, YA'AN
N1 - Funding Information:
This study was supported by the Innovation Talent Promotion Project Foundation of Shaanxi Province (grant no. 2018KJXX-058); the Hospital Fund of the Second Affiliated Hospital of the Health Science Center, Xi'an Jiaotong University [grant no. RC(GG)201708]; and the National Natural Science Foundation of China, NSFC (grant no. 81402583); Natural Science Foundation of Shaanxi Province (grant no. 2019JQ-969); Xi'an Jiaotong University Education Foundation, XJTUEF (grant no. xjj2018141).
Publisher Copyright:
© 2020 Spandidos Publications. All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - HIF-1α
KW - Lactic acid
KW - Microenvironment
KW - PD-L1
KW - Pancreatic cancer
KW - TAM
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UR - http://www.scopus.com/inward/citedby.url?scp=85092110564&partnerID=8YFLogxK
U2 - 10.3892/or.2020.7767
DO - 10.3892/or.2020.7767
M3 - Article
C2 - 33000216
AN - SCOPUS:85092110564
SN - 1021-335X
VL - 44
SP - 1885
EP - 1894
JO - Oncology reports
JF - Oncology reports
IS - 5
ER -