Colony-stimulating factor 1 (CSF1) is a key regulator of monocyte/macrophage differentiation that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). We show that CSF1 is expressed in human melanoma, and patients with metastatic melanoma have increased CSF1 in blood compared to healthy subjects. In tumors, CSF1 expression correlated with the abundance of CD8⁺ T cells and CD163⁺ TAMs. Human melanoma cell lines consistently produced CSF1 after exposure to melanoma-specific CD8⁺ T cells or T cell–derived cytokines in vitro, reflecting a broadly conserved mechanism of CSF1 induction by activated CD8⁺ T cells. Mining of publicly available transcriptomic data sets suggested co-enrichment of CD8⁺ T cells with CSF1 or various TAM-specific markers in human melanoma, which was associated with nonresponsiveness to programmed cell death protein 1 (PD1) checkpoint blockade in a smaller patient cohort. Combination of anti-PD1 and anti–CSF1 receptor (CSF1R) antibodies induced the regression of BRAF^V600E-driven, transplant mouse melanomas, a result that was dependent on the effective elimination of TAMs. Collectively, these data implicate CSF1 induction as a CD8⁺ T cell–dependent adaptive resistance mechanism and show that simultaneous CSF1R targeting may be beneficial in melanomas refractory to immune checkpoint blockade and, possibly, other T cell–based therapies.

集落刺激因子1（CSF1）是单核细胞/巨噬细胞分化的关键调节因子，可维持肿瘤相关巨噬细胞（TAM）的致瘤功能。我们显示，CSF1在人黑素瘤中表达，与健康受试者相比，转移性黑素瘤患者血液中的CSF1升高。在肿瘤中，CSF1表达与CD8 ⁺ T细胞和CD163 ⁺ TAM的含量相关。人类黑素瘤细胞系在体外暴露于黑素瘤特异性CD8 ⁺ T细胞或T细胞衍生的细胞因子后始终产生CSF1 ，反映了活化CD8 ⁺ T细胞诱导CSF1诱导的广泛保守机制。挖掘公开的转录组数据集提示CD8 ^+的共富集人黑素瘤中具有CSF1或各种TAM特异性标记物的T细胞，与较小患者队列中对程序性细胞死亡蛋白1（PD1）检查点封锁的无反应性相关。抗PD1和抗CSF1受体（CSF1R）抗体的组合诱导了BRAF ^V600E驱动的移植小鼠黑色素瘤的消退，其结果取决于有效消除TAM。总的来说，这些数据暗示CSF1诱导为依赖CD8 ⁺ T细胞的适应性耐药机制，并表明同时靶向CSF1R可能在难治性免疫检查点阻断的黑素瘤和其他可能基于T细胞的疗法中有益。