Frontiers in Immunology (Mar 2022)
Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm
- Erica A. K. DePasquale,
- Erica A. K. DePasquale,
- Erica A. K. DePasquale,
- Erica A. K. DePasquale,
- Daniel Ssozi,
- Daniel Ssozi,
- Marina Ainciburu,
- Jonathan Good,
- Jonathan Good,
- Jenny Noel,
- Jenny Noel,
- Martin A. Villanueva,
- Martin A. Villanueva,
- Martin A. Villanueva,
- Martin A. Villanueva,
- Martin A. Villanueva,
- Martin A. Villanueva,
- Charles P. Couturier,
- Charles P. Couturier,
- Charles P. Couturier,
- Alex K. Shalek,
- Alex K. Shalek,
- Alex K. Shalek,
- Alex K. Shalek,
- Alex K. Shalek,
- Alex K. Shalek,
- Sary F. Aranki,
- Hari R. Mallidi,
- Gabriel K. Griffin,
- Gabriel K. Griffin,
- Gabriel K. Griffin,
- Andrew A. Lane,
- Andrew A. Lane,
- Andrew A. Lane,
- Andrew A. Lane,
- Peter van Galen,
- Peter van Galen,
- Peter van Galen,
- Peter van Galen
Affiliations
- Erica A. K. DePasquale
- Division of Hematology, Brigham and Women’s Hospital, Boston, MA, United States
- Erica A. K. DePasquale
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Erica A. K. DePasquale
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Erica A. K. DePasquale
- Ludwig Center at Harvard, Harvard Medical School, Boston, MA, United States
- Daniel Ssozi
- Division of Hematology, Brigham and Women’s Hospital, Boston, MA, United States
- Daniel Ssozi
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Marina Ainciburu
- Hemato-Oncology Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain
- Jonathan Good
- Division of Hematology, Brigham and Women’s Hospital, Boston, MA, United States
- Jonathan Good
- Department of Human Biology, Sattler College, Boston, MA, United States
- Jenny Noel
- Division of Hematology, Brigham and Women’s Hospital, Boston, MA, United States
- Jenny Noel
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Martin A. Villanueva
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Martin A. Villanueva
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
- Martin A. Villanueva
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Martin A. Villanueva
- Division of Health Science & Technology, Harvard Medical School, Cambridge, MA, United States
- Martin A. Villanueva
- 0Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Martin A. Villanueva
- 1Ragon Institute, Harvard University, Massachusetts Institute of Technology, and Massachusetts General Hospital, Cambridge, MA, United States
- Charles P. Couturier
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Charles P. Couturier
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Charles P. Couturier
- Division of Health Science & Technology, Harvard Medical School, Cambridge, MA, United States
- Alex K. Shalek
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Alex K. Shalek
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Alex K. Shalek
- Division of Health Science & Technology, Harvard Medical School, Cambridge, MA, United States
- Alex K. Shalek
- 0Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Alex K. Shalek
- 1Ragon Institute, Harvard University, Massachusetts Institute of Technology, and Massachusetts General Hospital, Cambridge, MA, United States
- Alex K. Shalek
- 2Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States
- Sary F. Aranki
- 3Division of Thoracic and Cardiac Surgery, Brigham and Women’s Hospital, Boston, MA, United States
- Hari R. Mallidi
- 3Division of Thoracic and Cardiac Surgery, Brigham and Women’s Hospital, Boston, MA, United States
- Gabriel K. Griffin
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Gabriel K. Griffin
- 4Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, United States
- Gabriel K. Griffin
- 5Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
- Andrew A. Lane
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Andrew A. Lane
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Andrew A. Lane
- Ludwig Center at Harvard, Harvard Medical School, Boston, MA, United States
- Andrew A. Lane
- 6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Peter van Galen
- Division of Hematology, Brigham and Women’s Hospital, Boston, MA, United States
- Peter van Galen
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Peter van Galen
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Peter van Galen
- Ludwig Center at Harvard, Harvard Medical School, Boston, MA, United States
- DOI
- https://doi.org/10.3389/fimmu.2022.809414
- Journal volume & issue
-
Vol. 13
Abstract
The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.
Keywords
