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Published on: December 16, 2022
Loss of PTDSS1 in tumor cells improves immunogenicity and response to anti-PD-1 therapy
Jielin Liu1,2,3, Shelley Herbrich1,3, Sreyashi Basu3,4
1Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
PTDSS1 (phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of Ptdss1 in tumor cells increased expression of interferon-γ (IFN-γ)-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFN-γ stimulation in vitro. Loss of Ptdss1 in tumor cells also led to increased expression of MHC-I, enhanced cytotoxicity of CD8+ T cells, and increased frequency of an iNOS+ myeloid subset. A gene signature derived from the iNOS+ myeloid cell subset correlated with clinical benefit in patients treated with anti-PD-1 therapy. Moreover, genetic and pharmacological inhibition of Ptdss1 in different tumor models improved anti-PD-1 therapy. Together, our results provide insights on a therapeutic strategy for overcoming immunosuppression by inhibiting PTDSS1 and provide rationale for development of a combination immunotherapy strategy composed of PTDSS1 inhibition plus PD-1 blockade.
Insights
Inhibiting PTDSS1 (phosphatidylserine synthase 1) can enhance anti-PD-1 therapy by reducing tumor immunosuppression. This strategy boosts anti-tumor immunity and shows promise for combination immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Phosphatidylserine (PS) produced by PTDSS1 (phosphatidylserine synthase 1) mediates immunosuppression.
- Developing strategies to overcome tumor immunosuppression is crucial for effective cancer therapy.
Purpose of the Study:
- To identify novel targets for enhancing anti-PD-1 therapy.
- To investigate the role of PTDSS1 in tumor immunity and its potential as a therapeutic target.
Main Methods:
- In vivo CRISPR screening to identify PTDSS1 as a target.
- Analysis of gene expression changes (IFN-γ-regulated genes, MHC-I) upon Ptdss1 depletion.
- Assessment of CD8+ T cell cytotoxicity and myeloid cell subset frequency.
- Evaluation of PTDSS1 inhibition in preclinical tumor models with anti-PD-1 therapy.
Main Results:
- Depletion of Ptdss1 in tumor cells upregulated IFN-γ-regulated genes and MHC-I expression.
- Loss of Ptdss1 enhanced CD8+ T cell cytotoxicity and increased iNOS+ myeloid cells.
- A gene signature from iNOS+ myeloid cells correlated with clinical benefit in anti-PD-1 treated patients.
- PTDSS1 inhibition, genetic or pharmacological, improved anti-PD-1 therapy efficacy in various tumor models.
Conclusions:
- PTDSS1 inhibition is a viable strategy to overcome tumor immunosuppression.
- Targeting PTDSS1 can enhance anti-PD-1 immunotherapy by modulating the tumor microenvironment.
- Combination of PTDSS1 inhibition with PD-1 blockade offers a promising therapeutic approach.
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