Immunomodulatory roles of PARPs: Shaping the tumor microenvironment, one ADP-ribose at a time

Abstract

PARPs encompass a small yet pervasive group of 17 enzymes that catalyze a post-translational modification known as ADP-ribosylation. PARP1, the founding member, has received considerable focus; however, in recent years, the spotlight has shifted to other members within the PARP family. In this opinion piece, we first discuss surprising findings that some FDA-approved PARP1 inhibitors activate innate immune signaling in cancer cells that harbor mutations in the DNA repair pathway. We then discuss hot-off-the-press genetic and pharmacological studies that reveal roles for PARP7, PARP11, and PARP14 in immune signaling in both tumor cells and tumor-associated immune cells. We conclude with thoughts on tuning PARP1-inhibitor-mediated innate immune activation and explore the unrealized potential for small molecule modulators of other PARP family members as next-generation immuno-oncology drugs.

Figure 1.

Timeline of clinical and preclinical PARP inhibitor development. The chemical structures of clinical PARP1 inhibitors (olaparib, rucaparib, niraparib, and talazoparib) and their FDA approval dates are shown. Also shown are the chemical structures of MARylating PARP inhibitors (ITK7: PARP11 inhibitor; RBN2397: PARP7 inhibitor; RBN012759: PARP14 inhibitor; KMR206: PARP7 inhibitor; 1–1: PARP7 inhibitor; RBN-3143: PARP14 inhibitor) discussed in this review. RBN2397 and RBN-3143 are the first MARylating PARP inhibitors that entered the clinic.

Figure 2.

PARP1 trapping inhibitors stimulate cGAS–STING and downstream IFN-I signaling in BRCA1 null cancers. PARP1 trapping on chromatin leads to the accumulation of cytoplasmic DNA, resulting in micronuclei generation followed by activation of cGAS–STING. This leads to the phosphorylation and activation of TBK1 and IRF3, which leads to the transcription of the IFN-I IFNβ. IFNβ released in the tumor microenvironment leads to dendritic cell activation, which subsequently converts naïve T cells into cytotoxic T cells. IFNβ can also directly stimulate T cells, leading to their activation and cytotoxic T cell-mediated cancer cell death.

Figure 3.

PARP7 inhibitors enhance STING-dependent IFN-I signaling in cancer cells that express PARP7. Two models are proposed for the mechanism of action of PARP7 inhibitors on IFN-I signaling. In one model, PARP7 inhibitors reverse PARP7 MARylation-dependent suppression of IFNβ transcription. In another model, a PARP7: PARP7 inhibitor complex activates IFNβ transcription.

Figure 4.

PARP11 regulates IFNAR1 levels in cytotoxic T cells. (A) Treg cell-generated adenosine stimulates PARP11 transcription in cytotoxic T cells. PARP11 MARylates the βTrCP, which ubiquitylates IFNAR1, leading to its proteasomal degradation. (B) Knockout of PARP11 in T cells prevents IFNAR1 degradation, allowing them to respond to IFNβ, which leads to cytotoxic T cell-mediated cancer cell death.