PARP inhibitor treatment increased tumor infiltration by immunosuppressive macrophages in vivo.
Major Finding: PARP inhibitor treatment increased tumor infiltration by immunosuppressive macrophages in vivo.
Concept: Adding a CSF1R-blocking antibody (to prevent macrophage recruitment) to olaparib increased efficacy.
Impact: This work implies that macrophage infiltration is a surmountable barrier to PARP inhibitor resistance.
PARP inhibitors are approved for BRCA-mutant HER2-negative metastatic breast cancer, but although these drugs lead to greater progression-free survival and response rates than chemotherapy, the responses are not durable. In triple-negative breast cancer (TNBC), one possible explanation is the presence of immunosuppressive tumor-infiltrating M2 macrophages, suggesting to Mehta and colleagues that the combination of antibodies blocking CSF1R, the receptor for a cytokine called CSF1 that has macrophage function–promoting properties, might enhance the efficacy of PARP inhibitors in TNBC. They found that although BRCA1-mutant tumors from untreated patients had greater infiltration by T cells, including cytotoxic CD8+ T cells, than their BRCA1–wild-type counterparts, the BRCA1-mutant tumors also had greater infiltration by macrophages, which were the predominant immune cell type in these tumors. In vivo experiments showed that, despite the fact that treatment of a mouse model of BRCA1-mutant TNBC with the PARP inhibitor olaparib resulted in an initial modest tumor shrinkage and CD8+ T-cell infiltration, olaparib treatment was also associated with increased tumor macrophage infiltration, which may have been caused by increased expression of Csf1. Further investigation revealed that olaparib treatment altered the phenotypes of tumor-infiltrating macrophages, dividing them into one group highly expressing antitumor immunity–associated markers (CD80, CD86, CD40, and pTBK1) and another group highly expressing immunosuppressive markers (PD-L1 and CSF1R). In ex vivo experiments in which CD14+ monocytes (a group including macrophages) were induced to differentiate via exposure to IL4 and GM-CSF, cotreatment with olaparib increased monocyte differentiation into mature myeloid cells and induced expression of PD-L1 and CSF1R, but these effects were not observed when CD14+ monocytes were differentiated prior to olaparib exposure. Notably, in vivo experiments showed that combining a PARP inhibitor with a CSF1R-blocking antibody to prevent recruitment of immunosuppressive macrophages in a mouse model of BRCA1-mutant TNBC improved antitumor immunity and extended survival. Together, these findings imply an important role for immunosuppressive tumor-infiltrating macrophages in PARP inhibitor resistance and suggest a possible method to circumvent this problem.
Mehta AK, Cheney EM, Hartl CA, Pantelidou C, Oliwa M, Castrillon JA, et al. Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer 2020 Dec 14 [Epub ahead of print].
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