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.