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

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.