Loss of Ptdss1 in tumor cells improves anti-PD-1 therapy

<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⁺ 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2024

Authors dc:creator

• Liu, Jielin
• <p>0000-0001-9596-8943</p>

Contributors dc:contributor

• Padmanee Sharma, M.D., Ph.D.
• James P. Allison, Ph.D.
• Matthew M. Gubin, Ph.D.

• Immunotherapy
• anti-PD-1
• CRISPR Screen
• Ptdss1
• Bladder Cancer
• Cancer Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1336

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2393