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Loss of PTDSS1 in tumor cells improves immunogenicity and response to anti-PD-1 therapy [AmpSeq]

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 IFNγ-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFNγ stimulation in vitro. Loss of PTDSS1 in tumor cells also led to increased expression of MHC-I, which was associated with 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 new therapeutic strategy for overcoming immunosuppression by inhibiting PTDSS1 and provide rationale for development of a combination immunotherapy strategy comprised of PTDSS1 inhibition plus PD-1 blockade.

ORGANISM(S): synthetic construct Mus musculus

PROVIDER: GSE235588 | GEO | 2024/06/21

REPOSITORIES: GEO

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