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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Monday, November 11, 2024
According to Adam Nelson, PhD, of Brigham and Women’s Hospital, Boston, and colleagues, patients with BRCA1/2-associated breast cancer often demonstrate poor response to PARP inhibitors because of the rapid development of resistance via the induction of CSF-1R–positive suppressive tumor–associated macrophages. Their current preclinical study, presented during the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting (Abstract 821), aimed to determine whether CSF-1R inhibition could overcome PARP inhibitor resistance and to evaluate whether immune checkpoint inhibitors can increase the efficacy of this therapy combination.
“These data confirm targeting immunosuppressive tumor–associated macrophages induces favorable antitumor responses that enhance PARP inhibitor therapy, which immune checkpoint blockade can further enhance in PARP inhibitor–naive tumors,” concluded the investigators. “Importantly, our data show that targeting tumor-associated macrophages can overcome acquired PARP inhibitor resistance, defining a novel strategy addressing a critical unmet medical need for PARP inhibitor–treated patients with BRCA-associated breast cancer.”
The researchers treated mice bearing PARP inhibition–resistant or –naive, BRCA1-deficient, triple-negative breast cancer tumors with PARP inhibitors with or without CSF-1R inhibitors and/or anti–PD-1 therapy. Mice were evaluated for tumor growth and overall survival, and alterations in the tumor microenvironment were detected using RNA analysis and flow cytometry.
Tumors that were naive to PARP inhibition demonstrated significantly increased overall survival with PARP inhibitors plus CSF-1R inhibitors compared with PARP inhibitors alone. Further, the addition of anti–PD-1 therapy to this regimen yielded improved long-term tumor clearance. Increased antitumor immune responses related to T-cell chemotaxis and activation, as well as antigen presentation, were observed among tumors on the triplet regimen.
Compared with PARP inhibitor–naive tumors, the tumor-associated macrophages of PARP inhibitor–resistant tumors expressed lower levels of antigen presentation machinery and higher levels of PD-L1 and CSF-1R, suggesting increased immunosuppression, according to the researchers. CD4- and CD8-positive T cells also expressed higher levels of PD-1 in these tumors, implying increased exhaustion compared with PARP inhibitor–naive tumors.
Disclosure: Disclosure information was not provided.
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