To identify immune cell types that might predict a positive anti-PD-L1 response, Qu, Wen, Thomas et al. used a CT26 bilateral tumor model, allowing scRNAseq before and tumor growth monitoring following checkpoint blockade. A pre-treatment population of proinflammatory F480+MHCII+LY6Clo macrophage expressing Cxcl9 positively associated with anti-PD-L1 efficacy, and blocking Cxcl9 or its receptor Cxcr3 with antibodies ablated the anti-PD-L1 response. Analysis of patients treated with anti-PD-L1 (avelumab or atezolizumab) showed median overall survival increased 2.4- to 2.8-fold in patients with the highest Cxcl9 levels.
Contributed by Katherine Turner
ABSTRACT: 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(+)Ly6C(lo) 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.
Author Info: (1) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (2) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San
Author Info: (1) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (2) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (3) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (4) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (5) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (6) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (7) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (8) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (9) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. (10) Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA. Electronic address: shahram.salek-ardakani@pfizer.com.
