Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Autor:	DePasquale EAK; Division of Hematology, Brigham and Women's Hospital, Boston, MA, United States.; Department of Medicine, Harvard Medical School, Boston, MA, United States.; Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, United States., Ssozi D; Division of Hematology, Brigham and Women's Hospital, Boston, MA, United States.; Broad Institute of MIT and Harvard, Cambridge, MA, United States., Ainciburu M; Hemato-Oncology Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain., Good J; Division of Hematology, Brigham and Women's Hospital, Boston, MA, United States.; Department of Human Biology, Sattler College, Boston, MA, United States., Noel J; Division of Hematology, Brigham and Women's Hospital, Boston, MA, United States.; Broad Institute of MIT and Harvard, Cambridge, MA, United States., Villanueva MA; Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.; Division of Health Science & Technology, Harvard Medical School, Cambridge, MA, United States.; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, United States.; Ragon Institute, Harvard University, Massachusetts Institute of Technology, and Massachusetts General Hospital, Cambridge, MA, United States., Couturier CP; Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.; Division of Health Science & Technology, Harvard Medical School, Cambridge, MA, United States., Shalek AK; Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.; Division of Health Science & Technology, Harvard Medical School, Cambridge, MA, United States.; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, United States.; Ragon Institute, Harvard University, Massachusetts Institute of Technology, and Massachusetts General Hospital, Cambridge, MA, United States.; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States., Aranki SF; Division of Thoracic and Cardiac Surgery, Brigham and Women's Hospital, Boston, MA, United States., Mallidi HR; Division of Thoracic and Cardiac Surgery, Brigham and Women's Hospital, Boston, MA, United States., Griffin GK; Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, United States.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States., Lane AA; Department of Medicine, Harvard Medical School, Boston, MA, United States.; Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, United States.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States., van Galen P; Division of Hematology, Brigham and Women's Hospital, Boston, MA, United States.; Department of Medicine, Harvard Medical School, Boston, MA, United States.; Broad Institute of MIT and Harvard, Cambridge, MA, United States.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Mar 10; Vol. 13, pp. 809414. Date of Electronic Publication: 2022 Mar 10 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.809414
Abstrakt:	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. Competing Interests: AS reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, Third Rock Ventures, Hovione, Relation Therapeutics, FL82, and Dahlia Biosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 DePasquale, Ssozi, Ainciburu, Good, Noel, Villanueva, Couturier, Shalek, Aranki, Mallidi, Griffin, Lane and van Galen.)
Databáze:	MEDLINE
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