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Published on: July 21, 2018
Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma
Yang Chen1, Yu Zhou1, Ran Ren1
1Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, Chongqing, China.
Background:
While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy.
Methods:
Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment's cellular infiltration characteristics of the tumor. Furthermore, the lipid metabolism score (LMS) system was constructed, and based on the LMS system, we further performed screening for potential agents targeting lipid metabolism. The mechanism of MK1775 was further validated using RNA sequencing, co-culture technology, and in vivo experiments.
Results:
We developed an LSM system and identified a potential sensitizing agent, MK1775, which targets lipid metabolism and enhances the effects of anti-PD-1 treatment. Our results demonstrate that MK1775 inhibits tumor progression by influencing lipid crosstalk between tumor cells and tumor-associated macrophages and CD8+T cells, thereby increasing the effectiveness of anti-PD-1 treatment. Further, we found that MK1775 inhibited the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which on one hand downregulated FASN-mediated synthesis of fatty acids (FAs) to inhibit fatty acid oxidation of tumor-associated macrophages, and on the other hand, promoted IRF-mediated secretion of CXCL10 and CXCL11 to facilitate the infiltration of CD8+ T cells.
Conclusions:
These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches.
Insights
Abnormal lipid metabolism limits anti-programmed cell death protein-1 (PD-1) therapy effectiveness in lung cancer. Targeting lipid metabolism with MK1775 enhances anti-PD-1 treatment by modulating the tumor microenvironment and immune cell infiltration.
Area of Science:
- Oncology
- Immunology
- Metabolism
Background:
- Anti-programmed cell death protein-1 (PD-1) monotherapy shows limited efficacy in lung cancer, with response rates around 20%.
- Abnormal lipid metabolism in lung adenocarcinoma may impede anti-PD-1 therapy response.
- Understanding the interplay between lipid metabolism and the tumor immune microenvironment is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate lipid metabolism patterns in lung adenocarcinoma and their association with immune cell infiltration.
- To develop a lipid metabolism score (LMS) system for stratifying patients and identifying therapeutic targets.
- To evaluate the potential of targeting lipid metabolism to enhance anti-PD-1 immunotherapy efficacy.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) data to correlate lipid metabolism with immune cell infiltration.
- Construction of a lipid metabolism score (LMS) system.
- Screening for agents targeting lipid metabolism and validation of MK1775's mechanism using RNA sequencing, co-culture, and in vivo experiments.
Main Results:
- An LMS system was developed, identifying MK1775 as a potential sensitizing agent for anti-PD-1 therapy.
- MK1775 was shown to inhibit tumor progression by influencing lipid crosstalk between tumor cells, macrophages, and CD8+ T cells, thereby enhancing anti-PD-1 efficacy.
- MK1775 suppressed the PI3K/AKT/mTOR pathway, downregulating fatty acid synthesis and oxidation in macrophages while promoting CD8+ T cell infiltration via CXCL10/CXCL11 secretion.
Conclusions:
- Lipid metabolism plays a critical role in shaping the tumor microenvironment and influencing immunotherapy response.
- Targeting lipid metabolism presents a promising strategy to overcome resistance and sensitize lung cancer to anti-PD-1 therapy.
- Further research into manipulating lipid metabolism could lead to novel approaches for improving cancer treatment outcomes.
