Single-Cell RNA Sequencing Reveals a Dynamic Stromal Niche That Supports Tumor Growth
Sarah Davidson,
Mirjana Efremova,
Angela Riedel,
Bidesh Mahata,
Jhuma Pramanik,
Jani Huuhtanen,
Gozde Kar,
Roser Vento-Tormo,
Tzachi Hagai,
Xi Chen,
Muzlifah A. Haniffa,
Jacqueline D. Shields,
Sarah A. Teichmann
Affiliations
Sarah Davidson
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/Medical Research Council Research Centre, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
Mirjana Efremova
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Angela Riedel
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/Medical Research Council Research Centre, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK
Bidesh Mahata
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Department of Pathology, University of Cambridge, Cambridge, UK
Jhuma Pramanik
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Jani Huuhtanen
Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Gozde Kar
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Roser Vento-Tormo
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Tzachi Hagai
School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
Xi Chen
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Muzlifah A. Haniffa
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Jacqueline D. Shields
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/Medical Research Council Research Centre, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK; Corresponding author
Sarah A. Teichmann
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Cavendish Laboratory, University of Cambridge, JJ Thomson Ave, Cambridge CB3 0HE, UK; Corresponding author
Summary: Here, 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.
