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ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non-small cell lung cancer
Sophie O'Keefe1,2, Qiwei Wang1,2,3
1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Abstract:
Non-small cell lung cancer (NSCLC), the most common type of lung cancer, remains a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapy for NSCLC but only benefit a subset of patients. In this issue of the JCI, Jiao et al. revealed that acetyl-CoA acetyltransferase 1 (ACAT1) limited the efficacy of ICIs in NSCLC by impeding tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). Targeting ACAT1 in tumor cells reduced mitochondrial hypersuccinylation and oxidative stress, enhancing TLS abundance and improving the efficacy of ICIs in preclinical murine models of NSCLC.
Insights
Acetyl-CoA acetyltransferase 1 (ACAT1) limits immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC). Targeting ACAT1 enhances tertiary lymphoid structures (TLS) and improves ICI treatment outcomes in preclinical models.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) is a major cause of cancer mortality globally.
- Immune checkpoint inhibitors (ICIs) show promise for NSCLC but lack efficacy in many patients.
- The tumor microenvironment (TME) plays a critical role in ICI response.
Purpose of the Study:
- To investigate the role of acetyl-CoA acetyltransferase 1 (ACAT1) in regulating ICI efficacy in NSCLC.
- To explore the impact of ACAT1 on tertiary lymphoid structures (TLS) within the TME.
- To determine if targeting ACAT1 can enhance ICI therapy in NSCLC.
Main Methods:
- Utilized preclinical murine models of NSCLC.
- Investigated the effect of targeting ACAT1 on tumor cells.
- Assessed changes in mitochondrial hypersuccinylation and oxidative stress.
- Quantified TLS abundance in the TME.
- Evaluated the efficacy of combined ACAT1 inhibition and ICIs.
Main Results:
- ACAT1 was found to impede TLS formation in the NSCLC TME.
- Targeting ACAT1 reduced mitochondrial hypersuccinylation and oxidative stress in tumor cells.
- Inhibition of ACAT1 led to increased TLS abundance.
- Combined ACAT1 targeting and ICI therapy improved treatment efficacy in preclinical models.
Conclusions:
- ACAT1 is a key factor limiting ICI effectiveness in NSCLC by suppressing TLS.
- Targeting ACAT1 represents a potential strategy to enhance ICI therapy for NSCLC patients.
- Modulating ACAT1 could overcome resistance to immunotherapy in lung cancer.
