Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer

Abstract

Highlights d scRNA-seq analyses highlight conserved myeloid subsets in human and murine CRC d Two distinct TAM subsets show inflammatory and angiogenic signatures, respectively d Two distinct TAM subsets show differential sensitivity to CSF1R blockade d Anti-CD40 activates specific cDC1s and expands Th1-like and CD8 + memory T cells

TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment

“…It has been reported that LAYN and CCR8 are highly expressed in tumor-infiltrating Treg cells from colon cancer, non-small cell lung cancer, and liver cancer (6,33). We observed the consistently high expression of LAYN and CCR8 in Treg cells from four independent datasets (LIHC_GSE98638, NSCLC_GSE99254, COAD_GSE108989, and COAD_GSE146771_Smartseq2) (6,7,23,34), suggesting the tumor homogeneity in terms of cell phenotype signatures ( Figure 3D, Supplementary Figure S4). Besides the Treg cells, LAYN is also expressed in a subset of exhausted CD8T cells ( Figure 3D, Supplementary Figure S4).…”

The tumor microenvironment drives transcriptional phenotypes and their plasticity in metastatic pancreatic cancer

“…Specifically, TAMdirected therapies, such as anti-CSF1R antibodies, could be employed to selectively target transcriptionalsubtype-associated populations. 42,[53][54][55] However, while basal tumors associate with a potentially sensitive CSF1R-expressing population (C1QC+ TAM), classical tumors harbor TAMs that are resistant to such therapies (SPP1+ TAM). 42 Thus, just as we consider combinations to target malignant states, the TME will also likely require tailored combination therapies.…”

“…42,[53][54][55] However, while basal tumors associate with a potentially sensitive CSF1R-expressing population (C1QC+ TAM), classical tumors harbor TAMs that are resistant to such therapies (SPP1+ TAM). 42 Thus, just as we consider combinations to target malignant states, the TME will also likely require tailored combination therapies. These findings provide rationale for future clinical trials to employ highresolution phenotyping of malignant and non-malignant cells to stratify patients and track tumor evolution in response to therapy.…”

“…Relatively little is known about the structure and composition of the metastatic microenvironment in PDAC, and, more specifically, about how non-malignant heterogeneity associates with the basal to classical continuum. To 42,43 The first two PCs readily identified 3 TAM subsets: "monocyte-like" FCN1+, C1QC+, and SPP1+ macrophages (Extended Data Figure 6h). FCN1+ "monocyte-like" cells expressed high levels of IL1B and CCR2 and shared some features with CD14+ blood monocytes (CD300E, S100A8).…”

“…FCN1+ "monocyte-like" cells expressed high levels of IL1B and CCR2 and shared some features with CD14+ blood monocytes (CD300E, S100A8). 42 We next determined whether the 18 non-malignant cell types/states were represented evenly across the malignant basal-to-classical transcriptional continuum described in 3g). In addition to demonstrating that classical tumors are relatively more immune infiltrated, this analysis also identifies distinct microenvironmental phenotypes that co-vary with each PDAC transcriptional subtype and suggests opportunities to direct microenvironmental therapies in a subtype-specific manner.…”