Zhang, Li, and Skrzypczynska et al. used 10X and Smart-seq2 single-cell RNA sequencing platforms to profile shared immune cell subsets in CRC patients and in two CRC mouse models, treated with αCSF1R and agonist αCD40. Two distinct TAM populations were identified: CSF1R-sensitive TAMs (C1QC+) expressed antigen presentation and phagocytosis genes, and CSF1R-resistant TAMs (SPP1+) expressed angiogenesis genes. In CRC patients, a low C1QC+/high SPP1+ TAM gene signature was associated with worse survival. αCD40 treatment increased a Ccl22+ cDC1 population and memory CD8+ and Th1-like CD4+ TIL subsets.
Contributed by Katherine Turner
ABSTRACT: Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application toward dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a cDC population and increased Bhlhe40(+) Th1-like cells and CD8(+) memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.
Author Info: (1) Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (2) BIOPIC and School of Life Sciences, Pek
Author Info: (1) Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (2) BIOPIC and School of Life Sciences, Peking University, Beijing 100871, China. (3) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (4) Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (5) Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China. (6) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (7) Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (8) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (9) BIOPIC and School of Life Sciences, Peking University, Beijing 100871, China. (10) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (11) BIOPIC and School of Life Sciences, Peking University, Beijing 100871, China. (12) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (13) BIOPIC and School of Life Sciences, Peking University, Beijing 100871, China. (14) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (15) BIOPIC and School of Life Sciences, Peking University, Beijing 100871, China. (16) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (17) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (18) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (19) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (20) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (21) Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China. (22) Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China. (23) BIOPIC and School of Life Sciences, Peking University, Beijing 100871, China; Analytical Biosciences Limited, Beijing 100084, China. (24) BIOPIC and School of Life Sciences, Peking University, Beijing 100871, China. (25) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. (26) Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China. Electronic address: shenlong1977@163.com. (27) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. Electronic address: jegen@amgen.com. (28) Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; BIOPIC and School of Life Sciences, Peking University, Beijing 100871, China. Electronic address: zemin@pku.edu.cn. (29) Department of Inflammation and Oncology and Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, USA. Electronic address: xiyu@amgen.com.
