Sequencing B cells in B16-F10 tumors and lymph nodes, Bod et al. identified a cluster that expanded in the draining lymph nodes and expressed Havcr1 (encoding TIM-1) and other checkpoint genes. Havcr1 knockout in B cells increased frequencies of cytotoxic T cells in tumors and restricted tumor progression in multiple models. Anti-TIM-1 mAbs also slowed tumor growth. Havcr1-/- B cells upregulated antigen presentation and IFN-responsive genes, including IFNAR, and induced IFNγ expression while reducing Foxp3 in CD4+ T cells. The Havcr1 B cell signature was also found in human tumor datasets and was reduced in ICB-responding patients.
Contributed by Alex Najibi
ABSTRACT: The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth(1,2). Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.
Author Info: (1) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harva
Author Info: (1) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (2) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (3) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. BeiGene, Beijing, China. (4) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (5) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (6) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Division of Immunology and Pathophysiology, Medical University of Graz, Graz, Austria. (7) Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA. (8) Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA. (9) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (10) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (11) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (12) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (15) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (16) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (17) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (18) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (19) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (20) Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (21) Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA. (22) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Howard Hughes Medical Institute, Department of Biology and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (23) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (24) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Howard Hughes Medical Institute, Department of Biology and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (25) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. INSERM, Tours, France. Facult de Mdecine, Universit de Tours, Tours, France. (26) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aviv.regev.sc@gmail.com. Howard Hughes Medical Institute, Department of Biology and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. aviv.regev.sc@gmail.com. Genentech, San Francisco, CA, USA. aviv.regev.sc@gmail.com. (27) Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. vkuchroo@rics.bwh.harvard.edu. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. vkuchroo@rics.bwh.harvard.edu. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. vkuchroo@rics.bwh.harvard.edu.
