Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.

Autor: Hoffman SE; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Harvard-MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA.; PhD Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA., Dowrey TW; Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, MA 02118, USA.; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA., Villacorta Martin C; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA., Bi K; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Titchen B; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; PhD Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA., Johri S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; PhD Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA., DelloStritto L; Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA., Patel M; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Mackichan C; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Inga S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Chen J; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Grimaldi G; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Napolitano S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Wakiro I; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Wu J; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Yeung J; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Rotem A; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Sicinska E; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Shannon E; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Clancy T; Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Wang J; Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Denning S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Brais L; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Besson NR; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Pfaff KL; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Huang Y; Molecular Pathology Core Laboratory, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Kao KZ; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Rodig S; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Hornick JL; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Vigneau S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Park J; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Kulke MH; Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, MA 02118, USA., Chan J; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Van Allen EM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Murphy GJ; Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, MA 02118, USA.; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 Sep 29; Vol. 9 (39), pp. eadd9668. Date of Electronic Publication: 2023 Sep 27.
DOI: 10.1126/sciadv.add9668
Abstrakt: Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10 . Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.
Databáze: MEDLINE