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.

Author Info: (1) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Graduate School of Biomedical Sciences, University of T

Author Info: (1) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Graduate School of Biomedical Sciences, University of Texas MD Anderson UTHealth Houston, Houston, TX 77030, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (2) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (3) James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (4) James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (5) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (6) Independent Researcher, San Francisco, California, USA. (7) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (8) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (9) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (10) Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.