CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance

CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance

The use of colony-stimulating factor-1 receptor (CSF1R) inhibitors has been widely explored as a strategy for cancer immunotherapy due to their robust depletion of tumor-associated macrophages (TAMs). While CSF1R blockade effectively eliminates TAMs from the solid tumor microenvironment, its clinica...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 5; p. e2318534121
Main Authors: Banuelos, Allison, Zhang, Allison, Berouti, Hala, Baez, Michelle, Yılmaz, Leyla, Georgeos, Nardin, Marjon, Kristopher D, Miyanishi, Masanori, Weissman, Irving L
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 30-01-2024
Subjects:
Animals
Anticancer properties
Biological Sciences
Bone marrow
Cancer immunotherapy
CD47 Antigen
Colony-stimulating factor
CXCR2 protein
Effectiveness
Granulocytes
Immunosuppression
Immunotherapy
Macrophage colony-stimulating factor
Macrophages
Melanoma
Melanoma, Experimental
Myeloid-Derived Suppressor Cells
Phagocytosis
Solid tumors
Suppressor cells
Synergism
Tumor Microenvironment
Tumors
macrophages
tumor immunology
CD47 blockade
myeloid-derived suppressor cells
CXCR2
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Summary:The use of colony-stimulating factor-1 receptor (CSF1R) inhibitors has been widely explored as a strategy for cancer immunotherapy due to their robust depletion of tumor-associated macrophages (TAMs). While CSF1R blockade effectively eliminates TAMs from the solid tumor microenvironment, its clinical efficacy is limited. Here, we use an inducible CSF1R knockout model to investigate the persistence of tumor progression in the absence of TAMs. We find increased frequencies of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the bone marrow, throughout circulation, and in the tumor following CSF1R deletion and loss of TAMs. We find that G-MDSCs are capable of suppressing macrophage phagocytosis, and the elimination of G-MDSCs through CXCR2 inhibition increases macrophage capacity for tumor cell clearance. Further, we find that combination therapy of CXCR2 inhibition and CD47 blockade synergize to elicit a significant anti-tumor response. These findings reveal G-MDSCs as key drivers of tumor immunosuppression and demonstrate their inhibition as a potent strategy to increase macrophage phagocytosis and enhance the anti-tumor efficacy of CD47 blockade in B16-F10 melanoma.
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1A.B. and A.Z. contributed equally to this work.
Contributed by Irving L. Weissman; received October 24, 2023; accepted December 16, 2023; reviewed by Alberto Mantovani, Dmitry Gabrilovich, and Justin D. Lathia
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2318534121