Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer.

Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway.

Combination therapy targeting both innate and adaptive immunity improves survival in a pre-clinical model of ovarian cancer.

Background: Despite major advancements in immunotherapy among a number of solid tumors, response rates among ovarian cancer patients remain modest. Standard treatment for ovarian cancer is still surgery followed by taxane- and platinum-based chemotherapy. Thus, there is an urgent need to develop novel treatment options for clinical translation.

PARP Inhibitor Efficacy Depends on CD8 T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer.

Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8 T-cell infiltration and activation , and that CD8 T-cell depletion severely compromises antitumor efficacy.

Dysregulation in Actin Cytoskeletal Organization Drives Increased Stiffness and Migratory Persistence in Polyploidal Giant Cancer Cells.

Polyploidal giant cancer cells (PGCCs) have been observed by pathologists in patient tumor samples and are especially prominent in late stage, high grade disease or after chemotherapy. However, they are often overlooked due to their apparent dormancy. Recent research has shown PGCCs to be chemoresistant and express stem-like features, traits associated with disease progression and relapse.