PARP inhibitor plus radiotherapy reshape the immune suppressive microenvironment and potentiate the efficacy of immune checkpoint inhibitors in tumors with IDH1 mutation

Abstract

Isocitrate dehydrogenase 1 mutant (IDH1^mut) tumors respond poorly to immunotherapy, but are more sensitive to chemoradiotherapy and poly (ADP-ribose) polymerase inhibition (PARPi). Accordingly, some efforts have aimed to capitalize on the IDH1 mutation rather than reverse it. Moreover, radiotherapy (RT) and PARPi can stimulate antitumor immunity, raising the possibility of reversing the immunosuppression caused by IDH1 mutation while killing the tumor. To assess this possibility, we treated IDH1^mut tumors and cells with RT + PARPi. RT + PARPi showed enhanced efficacy over either modality alone both in vitro and in vivo. RT + PARPi induced more DNA damage and activated the cGAS-STING pathway more. IFNβ, CXCL10, and CCL5 were also more highly expressed at both the mRNA and protein levels. In two different tumor models, RT + PARPi increased infiltration and cytolytic function of CD8⁺ T cells, with one model also showing increased CD8⁺T cell proliferation. RT+PARPi also increased PD-L1 expression and enhanced checkpoint inhibition. Knocking out cGAS reversed the increased CD8⁺ T cell infiltration and the antitumor effect of RT+PARPi. We conclude that RT + PARPi reshapes the IDH1^mut tumor immunosuppressive microenvironment, thereby augmenting checkpoint inhibition.

Keywords: IDH1 mutation; Immunotherapy; PARP inhibitor; Radiotherapy; cGAS-STING.