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Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
DGAT1 mediates sex-specific CD8+ T cell antitumour responses
Alaa Madi1,2,3,4, Hui Shi5,6, Min Su7
1Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany. a.madi@dkfz-heidelberg.de.
Abstract:
Fatty acid (FA) oxidation plays an important role in T cell responses. However, whether DGAT1-mediated FA esterification to triacylglycerol also regulates T cell function remains unclear. Here we uncover a sexually dimorphic requirement for DGAT1 expression in CD8+ tumour-infiltrating lymphocyte function. In female mice, T cell-specific Dgat1 deficiency improves mitochondrial metabolic fitness and expands the pool of progenitor exhausted CD8+ T (Tex) cells to sustain antitumour responses. In male mice, however, Dgat1 deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8+ Tex cell death. We show that these effects are mediated by androgen receptor (AR) signalling. Deletion of Ar, overexpression of glutathione peroxidase 4, or inhibition of ER stress-induced cell death rescues Dgat1-deficient CD8+ T cell survival and promotes antitumour responses in male mice. Overall, this study suggests that DGAT1 detoxifies AR signalling in male mice to protect against ER stress-induced cell death and maintain T cell stemness, and uncovers sex-specific metabolic adaptations in the tumour microenvironment.
Insights
DGAT1 expression impacts CD8+ T cell anti-tumor responses differently in male and female mice. In females, DGAT1 deficiency enhances anti-tumor immunity, while in males, it causes T cell death via androgen receptor signaling.
Area of Science:
- Immunology
- Metabolic pathways
- Cancer research
Background:
- Fatty acid oxidation is crucial for T cell responses.
- The role of DGAT1-mediated fatty acid esterification in T cell function is not well understood.
Purpose of the Study:
- To investigate the role of DGAT1 in CD8+ T cell function within the tumor microenvironment.
- To explore potential sex differences in DGAT1's regulation of T cell responses.
Main Methods:
- Utilized a mouse model with T cell-specific Dgat1 deficiency.
- Analyzed CD8+ T cell metabolism, function, and survival in female and male mice.
- Investigated the role of androgen receptor (AR) signaling and endoplasmic reticulum (ER) stress.
Main Results:
- In female mice, Dgat1 deficiency improved mitochondrial function and expanded progenitor exhausted CD8+ T cells, enhancing anti-tumor responses.
- In male mice, Dgat1 deficiency induced fatty acid peroxidation, ER stress, and CD8+ T cell death, mediated by AR signaling.
- Interventions targeting AR signaling or ER stress rescued CD8+ T cell survival and anti-tumor responses in male mice.
Conclusions:
- DGAT1 plays a sexually dimorphic role in CD8+ T cell anti-tumor immunity.
- DGAT1 detoxifies AR signaling in male mice, preventing ER stress-induced cell death and maintaining T cell stemness.
- This study highlights sex-specific metabolic adaptations in the tumor microenvironment.
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