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 IFNγ-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1. Loss of PTDSS1 in tumor cells also led to increased expression of MHC-I, which was associated with increased expression of cytolytic function related genes in 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, PTDSS1 knockdown in two different tumor models improved anti-PD-1 therapy. Together, our results provide insights on a new therapeutic strategy for overcoming immunosuppression elicited by PS and provide rationale for development of a combination immunotherapy strategy comprised of PTDSS1 inhibition plus PD-1 blockade.
","abstract_html":"<p>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 IFNγ-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1. Loss of PTDSS1 in tumor cells also led to increased expression of MHC-I, which was associated with increased expression of cytolytic function related genes in CD8<sup>+</sup> T cells and increased frequency of an iNOS<sup>+</sup> myeloid subset. A gene signature derived from the iNOS<sup>+</sup> myeloid cell subset correlated with clinical benefit in patients treated with anti-PD-1 therapy. Moreover, PTDSS1 knockdown in two different tumor models improved anti-PD-1 therapy. Together, our results provide insights on a new therapeutic strategy for overcoming immunosuppression elicited by PS and provide rationale for development of a combination immunotherapy strategy comprised of PTDSS1 inhibition plus PD-1 blockade.</p>","abstract_has_math":false,"creators":["Liu, Jielin","0000-0001-9596-8943
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"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1336"],"dc:subject":["Immunotherapy","anti-PD-1","CRISPR Screen","Ptdss1","Bladder Cancer","Cancer Biology"],"dc:title":["Loss of Ptdss1 in tumor cells improves anti-PD-1 therapy"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:48:59Z"}