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.
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DOI：
10.1073/pnas.2318534121
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发表时间：
2024-01
影响因子：
11.1
通讯作者：
A. Banuelos;Allison Zhang;Hala Berouti;Michelle Baez;Leyla Yılmaz;Nardin Georgeos;Kristopher D Marjon-Kristop
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文献类型：
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作者：
A. Banuelos;Allison Zhang;Hala Berouti;Michelle Baez;Leyla Yılmaz;Nardin Georgeos;Kristopher D Marjon-Kristop
集落刺激因子-1受体（CSF 1 R）抑制剂的使用已被广泛探索，作为癌症免疫治疗的策略，因为它们能有效地消除肿瘤相关巨噬细胞（TAM）。虽然CSF 1 R阻断有效地从实体瘤微环境中消除TAM，但其临床疗效有限。在这里，我们使用诱导型CSF 1 R敲除模型来研究在没有TAM的情况下肿瘤进展的持续性。我们发现粒细胞髓源性抑制细胞（G-MDSC）在骨髓中，整个循环，并在肿瘤后CSF 1 R缺失和损失的TAM的频率增加。我们发现G-MDSC能够抑制巨噬细胞吞噬作用，并且通过CXCR 2抑制消除G-MDSC增加了巨噬细胞清除肿瘤细胞的能力。此外，我们发现CXCR 2抑制和CD 47阻断的组合疗法协同作用以引起显著的抗肿瘤应答。这些发现揭示了G-MDSC是肿瘤免疫抑制的关键驱动因素，并证明其抑制是增加巨噬细胞吞噬作用和增强B16-F10黑色素瘤中CD 47阻断的抗肿瘤功效的有效策略。
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.