Blocking CCR1+ macrophages overcomes resistance to immune checkpoint inhibitors in melanoma

Chemokines and their receptors play a pivotal role in shaping the tumor microenvironment (TME) and modulating immune responses by orchestrating immune cell recruitment, spatial positioning, and facilitating cell-cell interactions. However, the exact mechanisms underlying chemokine signaling across different cell populations within the TME remain poorly understood. In this study, we utilized multiple-omics approaches to explore the relationship between CCR1 + macrophages, CD8 + exhausted T (Tex) cells, and immune checkpoint blockade (ICB) therapy response, as well as the role of chemokine signaling in the formation of CCR1 + macrophage and CD8 + Tex cell niches. We found that CCR1 + macrophages were closely associated with ICB outcomes in melanoma. Additionally, combination therapy with a CCR1 antagonist and anti-PD-1 monoclonal antibody significantly reduced tumor burden in melanoma mouse models, which was attributed to the substantial depletion of CD8 + Tex cells. Further, CCR1 + macrophages were found to co-localize with CD8 + Tex cells in human melanoma tissue, and the CCR1 + macrophage-CD8 + Tex cell niche was correlated with ICB treatment response in mice. Importantly, the CCR1-CCL3 axis was identified as a critical mediator in the formation of this niche. Overall, our study underscores the spatial relationship between CCR1 + macrophages and CD8 + Tex cells in ICB therapy, providing a promising strategy to overcome ICB resistance in melanoma.