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Published on: January 31, 2025
Lysosomal lipid peroxidation regulates tumor immunity
Monika Bhardwaj1, Jennifer J Lee1, Amanda M Versace1
1Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract:
Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naive T cells and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate that LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.
Insights
Palmitoyl-protein thioesterase 1 (PPT1) inhibitors induce lysosomal lipid peroxidation and cell death. This novel cell death pathway enhances anti-tumor immunity, suggesting new cancer treatment strategies.
Area of Science:
- Cell Biology
- Immunology
- Biochemistry
Background:
- Palmitoyl-protein thioesterase 1 (PPT1) inhibitors can cause cell death, but the precise mechanism remains unclear.
- Standard programmed cell death pathways are not implicated in PPT1 inhibitor-induced cytotoxicity.
Purpose of the Study:
- To elucidate the mechanism of cell death induced by PPT1 inhibition.
- To investigate the immunogenic properties of PPT1 inhibitor-treated cells and their potential in cancer therapy.
Main Methods:
- Utilized PPT1 inhibitors (e.g., DC661) in cell culture and mouse models.
- Assessed cell death pathways, lysosomal function, lipid peroxidation, and immune responses.
- Investigated the role of the lysosomal cysteine transporter MFSD12 and the antioxidant N-acetylcysteine (NAC).
Main Results:
- PPT1 inhibition triggers lysosomal lipid peroxidation (LLP), leading to lysosomal membrane permeabilization and cell death.
- Cell death is rescued by NAC, highlighting the role of oxidative stress, and requires the lysosomal transporter MFSD12.
- PPT1 inhibition induces cell-intrinsic immunogenicity, enhancing T cell-mediated anti-tumor responses in vivo, particularly in "immune hot" tumors.
Conclusions:
- Lysosomal lipid peroxidation drives a unique form of immunogenic cell death.
- PPT1 inhibition represents a promising strategy for enhancing cancer immunotherapy, especially when combined with antioxidants like NAC.
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