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Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
Published on: August 2, 2021
Targeting PID1 generates oxysterols to switch macrophage cell fates for improved antitumor immunity
Yuxiao Zheng1,2, Qi Wang3, Chen Dong1,2
1State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Abstract:
Disordered cholesterol-oxysterol profiles are observed in the tumor microenvironment, yet their roles in tumor-associated macrophages (TAMs) remain underexplored. This study reveals that TAMs across human pan-cancers exhibit elevated phosphotyrosine interaction domain-containing protein 1 (PID1) expression and prominent immunosuppressive gene signatures. PID1 deficiency in myeloid cells upregulates low-density lipoprotein (LDL) receptor expression, thereby promoting LDL uptake and intracellular accumulation of free cholesterol and reactive oxygen species (ROS). Increased ROS drives cholesterol oxidation to generate the oxysterols 5α,6α-epoxycholesterol (5α,6α-EC) and 7β-hydroxycholesterol (7β-OHC), which inhibit mTOR-STAT6 signaling in macrophages. Pid1 deletion switches immunosuppressive macrophages toward an antitumor subtype that downregulates arginase 1 expression while upregulating proinflammatory cytokines, thereby potentiating CD8+ T cell-mediated immunosurveillance across multiple tumor types. Moreover, combination treatment with the oxysterol and chemotherapeutic agent 5-fluorouracil produces synergistically enhanced antitumor effects. Previous studies showed that cholesterol-derived oxysterols differentially regulate macrophage cell fates, with 25-OHC promoting the protumor and immunosuppressive phenotype of TAMs. Targeting PID1 reroutes cholesterol and ROS metabolism toward the production of 5α,6α-EC and 7β-OHC in TAMs, representing a promising immunometabolic strategy to restore antitumor immunosurveillance.
Insights
Targeting phosphotyrosine interaction domain-containing protein 1 (PID1) in tumor-associated macrophages (TAMs) reprograms their metabolism. This shift enhances antitumor immunity by altering cholesterol and reactive oxygen species (ROS) pathways.
Area of Science:
- Immunology
- Cancer Biology
- Metabolic Pathways
Background:
- Tumor microenvironments exhibit altered cholesterol-oxysterol profiles, with unclear roles in tumor-associated macrophages (TAMs).
- TAMs in human pan-cancers show increased phosphotyrosine interaction domain-containing protein 1 (PID1) and immunosuppressive gene signatures.
Purpose of the Study:
- To investigate the role of PID1 in TAMs and its impact on macrophage function and antitumor immunity.
- To explore PID1's influence on cholesterol metabolism and subsequent oxysterol generation within TAMs.
Main Methods:
- Analysis of PID1 expression and gene signatures in TAMs from human pan-cancers.
- Investigation of PID1 deficiency effects on myeloid cell LDL receptor expression, cholesterol uptake, and ROS production.
- Assessment of oxysterol generation (5α,6α-EC and 7β-OHC) and their impact on macrophage signaling pathways (mTOR-STAT6).
- Evaluation of macrophage phenotype switching and its effect on CD8+ T cell-mediated immunosurveillance.
- Combination treatment studies with oxysterols and 5-fluorouracil.
Main Results:
- PID1 deficiency in myeloid cells increases LDL receptor expression, leading to enhanced LDL uptake, free cholesterol, and ROS accumulation.
- Increased ROS promotes cholesterol oxidation to 5α,6α-epoxycholesterol (5α,6α-EC) and 7β-hydroxycholesterol (7β-OHC), inhibiting mTOR-STAT6 signaling.
- Loss of PID1 switches TAMs from an immunosuppressive to an antitumor phenotype, reducing arginase 1 and increasing proinflammatory cytokines.
- This phenotype switch enhances CD8+ T cell-mediated immunosurveillance in various tumor types.
- Combined treatment with oxysterols and 5-fluorouracil shows synergistic antitumor effects.
Conclusions:
- Targeting PID1 in TAMs reroutes cholesterol and ROS metabolism, generating specific oxysterols (5α,6α-EC, 7β-OHC) that promote antitumor immunity.
- This immunometabolic strategy effectively restores antitumor immunosurveillance by reprogramming TAMs.
- The findings suggest PID1 as a potential therapeutic target for cancer immunotherapy.
