Abstract
SummaryHere, using single-cell RNA sequencing, we examine the stromal compartment in murine melanoma and draining lymph nodes (LNs) at points across tumor development, providing data at http://www.teichlab.org/data/. Naive lymphocytes from LNs undergo activation and clonal expansion within the tumor, before PD1 and Lag3 expression, while tumor-associated myeloid cells promote the formation of a suppressive niche. We identify three temporally distinct stromal populations displaying unique functional signatures, conserved across mouse and human tumors. Whereas “immune” stromal cells are observed in early tumors, “contractile” cells become more prevalent at later time points. Complement component C3 is specifically expressed in the immune population. Its cleavage product C3a supports the recruitment of C3aR+ macrophages, and perturbation of C3a and C3aR disrupts immune infiltration, slowing tumor growth. Our results highlight the power of scRNA-seq to identify complex interplays and increase stromal diversity as a tumor develops, revealing that stromal cells acquire the capacity to modulate immune landscapes from early disease.
Highlights
To aid their growth and development, malignant cells cultivate a supporting niche of ‘‘normal’’ cells, known as the tumor microenvironment (TME)
Using a unique database of known ligand-receptor interactions, we investigated communication between different stromal and immune populations to reveal the complex interplay between the immune stromal subset, macrophages, and T cells, which contributes to T cell dysfunction
Identification of Immune and Stromal Populations within the Developing TME To reconstruct the immune composition of a developing TME, we injected B16-F10 melanoma cells into mice
Summary
To aid their growth and development, malignant cells cultivate a supporting niche of ‘‘normal’’ cells, known as the tumor microenvironment (TME) This niche comprises non-immune cells such as fibroblasts, blood and lymphatic endothelial cells, and numerous immune populations (Turley et al, 2015). The balance of anti-tumor versus pro-tumor leukocytes can dictate tumor fate (Galon et al, 2006; Sato et al, 2005), and suppressive populations can persist to support immune escape and prevent tumor clearance While immunotherapies such as anti-CTLA4, antiPD1, and anti-PD-L1 show efficacy in a large number of melanoma patients, a significant proportion do not respond to this treatment (Brahmer et al, 2012; Hamid et al, 2013; Hodi et al, 2010; Topalian et al, 2012). The evolving TME is extremely dynamic, continually adapting to both soluble and mechanical cues, inducing significant heterogeneity within the stromal compartment (Junttila and de Sauvage, 2013)
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