Liu et al. performed an in vivo CRISPR screen under selective pressure of anti-PD-1 therapy, and identified phosphatidylserine synthase 1 (PTDSS1) as a tumor-specific gene involved in regulating anti-PD-1 response. Both genetic and pharmacological inhibition of Ptdss1 sensitized the MB49 tumor to anti-PD-1. Loss of Ptdss1 increased IFNγ response and antigen presentation in tumor cells, promoted a pro-inflammatory TME with increased infiltration of CD4+ T cells and iNOS+ myeloid cells, and enhanced sensitivity to CD8+ T cytotoxicity. In humans, PTDSS1 was found to be amplified across cancer types, and correlated with poor response to anti-PD-1 treatment.
Contributed by Shishir Pant
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-_ (IFN-_)-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFN-_ 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.
