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Joyce F. Liu, MD, MPH
Joyce F. Liu, MD, MPH
Posted: Tuesday, January 21, 2025
Samar Elorbany, MBBCh, MSc, MD, PhD, of Barts Cancer Institute, Queen Mary University of London, and colleagues previously reported that neoadjuvant chemotherapy impacts the activity of immune cells in patients with high-grade serous ovarian cancer (HGSOC). Their most recent analysis, published in Nature Communications, used HGSOC metastases to examine the effect of platinum-based chemotherapy on the tumor microenvironment and how biomarkers can be targeted to enhance said chemotherapy.
“We believe our work has a translational potential, as it represents the preclinical work for possible successful treatment combinations, especially the triple combination,” suggested the investigators. "Both our immune targets are expressed in BRCA-mutated/homologous DNA repair–deficient (HRD) and non-HRD tumors, and our findings could be relevant to other human cancers expressing high levels of STAB123 and regulatory T cells or showing upregulation after platinum-based chemotherapy.”
A total of 64,097 immune-enriched cells from site-matched, patient-matched, HGSOC metastases were obtained from seven patients. An additional 69,781 cells from chemotherapy-treated and controlled omental tumors that replicated the human tumor microenvironment were analyzed for comparison. HGSOC cell lines were grown in mouse cell line media and subsequently injected into three syngeneic mouse models—HGS2, 30200, and 60577—to validate the efficacy of potential targets in combination with chemotherapy.
Neoadjuvant chemotherapy–induced overexpression of stabilin-1—a macrophage scavenger receptor—was identified on FOX3 and macrophages in regulatory T cells, which was confirmed at the protein level. Ultimately, stabilin-1 inhibition was observed to induce antitumor macrophages, whereas FOXP3 antisense oligonucleotide appeared to repolarize regulatory T cells to an effector cell phenotype.
The combination of chemotherapy with an anti–stabilin-1 antibody and/or FOXP3 antisense oligonucleotide was found to significantly prolong the survival of mice in two models as well as progression-free survival in a third model. Of note, the anti–stabilin-1 antibody enriched the tumors with CXCL9-positive macrophages, whereas FOXP3 antisense oligonucleotide increased the infiltration of CD4-positive helper T cells.
Disclosure: Dr. Elorbany reported no conflicts of interest. For full disclosures of the other study authors, visit nature.com.
