Baseline Frequency of Inflammatory Cxcl9-Expressing Tumor-Associated Macrophages Predicts Response to Avelumab Treatment

The tumor microenvironment is rich with immune-suppressive macrophages that are associated with cancer progression and resistance to immune checkpoint therapy. Using pre-treatment tumor biopsies complemented with single-cell RNA sequencing (RNA-seq), we characterize intratumoral immune heterogeneity to unveil potential mechanisms of resistance to avelumab (anti-PD-L1). We identify a proinflammatory F480+MHCII+Ly6Clo macrophage population that is associated with response rather than resistance to avelumab. These macrophages are the primary source of the interferon-inducible chemokine Cxcl9, which facilitates the recruitment of protective Cxcr3+ T cells. Consequently, the efficacy of avelumab in mouse tumor models is dependent on Cxcr3 and Cxcl9, and baseline levels of Cxcl9 in patients treated with avelumab are associated with clinical response and overall survival. These data suggest that, within the broadly immune-suppressive macrophage compartment, a pro-inflammatory population exists that promotes responsiveness to PD-L1 blockade. [Display omitted] •CT26 cancer elicits a heterogeneous response to avelumab (anti-PD-L1) treatment•A bilateral tumor model identifies cell types that predict response to avelumab•A Cxcl9+ tumor-associated macrophage population predicts response to avelumab•Blockade of Cxcl9 converts avelumab responders to non-responders Qu and colleagues combine a bilateral tumor model approach with scRNA-seq to identify immune cell types that predict response to the immune checkpoint inhibitor avelumab (anti-PD-L1). A Cxcl9-expressing, tumor-associated myeloid population is present in tumors before treatment and predicts a favorable outcome in pre-clinical and clinical studies.