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Study suggests co-targeting of G-MDSCs and macrophages to treat melanoma

Allison Banuelos, Ludwig Cancer Research Stanford
Allison Banuelos
Allison Zhang, Ludwig Cancer Research Stanford
Allison Zhang
Irv Weissman, Ludwig Cancer Research Stanford
Irv Weissman

Colony-stimulating factor-1 receptor (CSF1R) inhibitors, which deplete a subset of immune cells that support cancer growth known as tumor-associated macrophages (TAMs), have had limited success in patients. Ludwig Stanford’s Allison Banuelos, Allison Zhang and Director Irv Weissman explored the causes of such failure using a mouse model in which the CSF1R could be inducibly deleted. They reported in a January paper in PNAS that systemic and intratumoral increases in numbers of granulocytic myeloid-derived suppressor cells (G-MDSCs) contribute significantly to resistance to CSF1R inhibitors in a mouse model by undermining the ability of macrophages to gobble up cancer cells and debris (phagocytosis), which is a key function of the antitumor version of these cells. Targeting G-MDSCs by CXCR2 inhibition improved the ability of macrophages to attack cancer cells. Combining CXCR2 inhibition with CD47 blockade—a therapy developed by Irv’s group, now in clinical development, that silences a “don’t eat me” signal transmitted by cancer cells to macrophages—boosted macrophage phagocytosis and delayed tumor progression in a mouse model of melanoma. This indicates G-MDSCs play a central role in melanoma’s suppression of immune responses. The researchers suggest combining CD47 and CXCR2 inhibition might be a potent strategy to boost the efficacy of CD47 blockade for cancer therapy.

CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance
PNAS, 2024 January 23

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