LAUSR

BRCA1 is a tumor-suppressor gene that encodes proteins involved in the repair of DNA double-strand breaks by way of the homologous recombination repair pathway. BRCA1 mutations occur in approximately 5% of breast cancer (BC) patients. This mutation renders cells susceptible to chromosomal instability through defective DNA break repair, leading to increased risk of triple-negative BC (TNBC). Two years ago, the FDA approved poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of BRCA-associated human epidermal growth factor receptor 2 (HER2)-negative metastatic BC. Approval was based on data from OlympiAD, where response rates and progression-free survival (PFS) were superior to standard chemotherapy. Mehta et al. published a motivating article in Nature Cancer showing the effects of PARP inhibition on macrophages in a preclinical model of BRCA1-deficient TNBC. First, they showed in tissue specimens from untreated TNBC patients that tumors with mutated BRCA1 had significantly more T cells and macrophages than BRCA-WT. Furthermore, an extensive characterization of tumor macrophages in a mouse of BRCA1-deficient TNBC revealed that macrophage numbers increase further after PARP inhibitor treatment, hence, olaparib modulated the tumor microenvironment. Interestingly, they showed that olaparib treatment drove both proand antitumor phenotypes. On the one hand, olaparib induced an up-regulation of CD80 and CD40 and an activation of the stimulator of interferon response CGAMP interactor (STING) pathway of macrophages, resulting in an antitumor phenotype. But, on the other hand, a concomitant increase in levels of immune-suppressive markers [programmed death-ligand 1 (PD-L1) and colony-stimulating factor 1 receptor (CSF1R)] and a modulation of macrophage metabolism (switch from glycolysis to lipid metabolism) were observed, which would be related to limit antitumor activity. Anti-CSF1R therapy has been shown to deplete a subset of macrophages, especially tumor-promoting macrophages. They hypothesized that targeting CSFR1þ macrophages would enhance olaparib activity. To address this premise, they combined anti-CSF1R and olaparib in a BRCA1deficient TNBC mouse model. As they expected, the combination reduced the number of CD206þ and PD-L1þ CSF1Rþ protumor macrophages and restored their glycolytic metabolism, which translates to improved response duration and PFS compared with treatment with olaparib alone in preclinical models. Overall, the manuscript suggests that combining PARP inhibitors with anti-CSF1R therapy reduces immune-