Therapeutic targeting of PARP with immunotherapy in acute myeloid leukemia

Abstract

Targeting the poly (ADP-ribose) polymerase (PARP) protein has shown therapeutic efficacy in cancers with homologous recombination (HR) deficiency due to BRCA mutations. Only small fraction of acute myeloid leukemia (AML) cells carry BRCA mutations, hence the antitumor efficacy of PARP inhibitors (PARPi) against this malignancy is predicted to be limited; however, recent preclinical studies have demonstrated that PARPi monotherapy has modest efficacy in AML, while in combination with cytotoxic chemotherapy it has remarkable synergistic antitumor effects. Immunotherapy has revolutionized therapeutics in cancer treatment, and PARPi creates an ideal microenvironment for combination therapy with immunomodulatory agents by promoting tumor mutation burden. In this review, we summarize the role of PARP proteins in DNA damage response (DDR) pathways, and discuss recent preclinical studies using synthetic lethal modalities to treat AML. We also review the immunomodulatory effects of PARPi in AML preclinical models and propose future directions for therapy in AML, including combined targeting of the DDR and tumor immune microenvironment; such combination regimens will likely benefit patients with AML undergoing PARPi-mediated cancer therapy.

Keywords: AML; DNA repair; PARP; immuotherapy; synergisctic effects.

FIGURE 1

The classical mechanism of PARPi activity in cancer therapy. (A) Single-strand breaks are identified and repaired by PARP1. (B) PARPi induces double-strand break (DSB) formation by inhibiting PARP enzyme activity or PARP trapping. In HR-competent cells, DSBs can be repaired by HR, leading to cell survival. In HR-deficient cells, DSBs cannot be repaired correctly by error-prone NHEJ, leading accumulation of replication fork collapse and, ultimately, cell death.

FIGURE 2

Specific genetic alterations that modify therapeutic sensitivity to PARPi in AML. Based on previous studies, AML cells carrying mutations of, or deficient for, RUNX1-RUNX1T1, PML-RARα, IDH1/2, STAG2, and FLT3-ITD/Tet2 ^−/− genes are sensitive to PARP inhibition. In contrast, AML cells carrying KMT2A-MLLT3 or FLT3-ITD/Dnmt3a ^−/− are not responsive to PARP inhibition.

FIGURE 3

Immune evasion mechanisms of AML blasts. Schematic illustration summarizing intrinsic and extrinsic AML immune evasion mechanisms. AML blasts can impede T and NK cell effector functions by overexpressing inhibitory T cell ligands, such as PD-L1, Gal9, CD155, CD122, and CD86, or by overexpressing the NKG2D ligand, NKG2DL. Meanwhile, AML blasts can reduce the expression of antigen presentation molecules; thereby suppressing their presentation to dendritic cells (DCs). Furthermore, AML blasts can alter cytokine secretion in the microenvironment and release of reactive oxygen species (ROS), indoleamine 2,3-dioxygenase-1 (IDO1), arginase II (Arg II), and extracellular vesicles (EVs), into the bone marrow (BM) niche. This, in turn, can promote T cell exhaustion and apoptosis, drive the expansion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and induce switch of macrophages from M1 to the tumor-promoting M2 phenotype.

FIGURE 4

The roles PARPi or ATRi in immune modulation. Multiple studies have exploited the immunogenic properties of anticancer drugs to enhance tumor immunogenicity. The represented approach is through activating cytosolic immunity pathways. In this pathway, PARPi or ATRi activate cGAS-STING signals and mediate the secretion of IFN-γ and other cytokines. Further, IFN-γ secretion can induce NKG2DL expression, leading to interaction of NKG2DL with NKG2D and subsequently augmenting NK cell-mediated cell killing.