Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors

Evasion of anti-tumor immunity and resistance to therapies in solid tumors are aided by immune-suppressive tumor microenvironment (TME). We found that TME factors such as regulatory T cells and adenosine downregulated type I interferons (IFN1) receptor IFNAR1 on CD8(+) cytotoxic T lymphocytes (CTL). These events relied upon poly-ADP ribose polymerase-11 (PARP11), which was induced in the intratumoral CTL and acted as a key regulator of the immune suppressive 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 (CAR) T cells. CAR CTL engineered to inactivate PARP11 demonstrated a superior efficacy against solid tumors. These findings highlight the role of PARP11 in the immune suppressive TME and provide a proof of principle for targeting this pathway to optimize immune therapies.