| First Author | Zhang H | Year | 2022 |
| Journal | Nat Cancer | Volume | 3 |
| Issue | 7 | Pages | 808-820 |
| PubMed ID | 35637402 | Mgi Jnum | J:354553 |
| Mgi Id | MGI:7327363 | Doi | 10.1038/s43018-022-00383-0 |
| Citation | Zhang H, et al. (2022) Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors. Nat Cancer 3(7):808-820 |
| abstractText | Evasion of antitumor immunity and resistance to therapies in solid tumors are aided by an immunosuppressive tumor microenvironment (TME). We found that TME factors, such as regulatory T cells and adenosine, downregulated type I interferon receptor IFNAR1 on CD8(+) cytotoxic T lymphocytes (CTLs). These events relied upon poly-ADP ribose polymerase-11 (PARP11), which was induced in intratumoral CTLs and acted as a key regulator of the immunosuppressive TME. Ablation of PARP11 prevented loss of IFNAR1, increased CTL tumoricidal activity and inhibited tumor growth in an IFNAR1-dependent manner. Accordingly, genetic or pharmacologic inactivation of PARP11 augmented the therapeutic benefits of chimeric antigen receptor T cells. Chimeric antigen receptor CTLs engineered to inactivate PARP11 demonstrated a superior efficacy against solid tumors. These findings highlight the role of PARP11 in the immunosuppressive TME and provide a proof of principle for targeting this pathway to optimize immune therapies. |
