B-cell-specific checkpoint molecules that regulate anti-tumour immunity

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-sequencin...

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Published in:	Nature (London) Vol. 619; no. 7969; pp. 348 - 356
Main Authors:	Bod, Lloyd, Kye, Yoon-Chul, Shi, Jingwen, Torlai Triglia, Elena, Schnell, Alexandra, Fessler, Johannes, Ostrowski, Stephen M., Von-Franque, Max Y., Kuchroo, Juhi R., Barilla, Rocky M., Zaghouani, Sarah, Christian, Elena, Delorey, Toni Marie, Mohib, Kanishka, Xiao, Sheng, Slingerland, Nadine, Giuliano, Christopher J., Ashenberg, Orr, Li, Zhaorong, Rothstein, David M., Fisher, David E., Rozenblatt-Rosen, Orit, Sharpe, Arlene H., Quintana, Francisco J., Apetoh, Lionel, Regev, Aviv, Kuchroo, Vijay K.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 13.07.2023 Nature Publishing Group
Subjects:	13/1 13/31 45 45/91 631/114 631/250/580 631/67/1813/1634 64/60 Adaptive immunity Animals Antigen Presentation Antigens B-Lymphocytes - cytology B-Lymphocytes - immunology B-Lymphocytes - metabolism Cancer CD223 antigen Cell activation Cell surface Cells Deletion Effector cells Flow Cytometry Gene sequencing Humanities and Social Sciences Immunoglobulins Immunotherapy Interferon Type I Lymph nodes Lymph Nodes - cytology Lymph Nodes - immunology Lymphocyte Activation Lymphocytes Lymphocytes B Lymphocytes T Melanoma Melanoma - immunology Melanoma - pathology Melanoma - prevention & control Melanoma, Experimental - immunology Melanoma, Experimental - pathology Mice multidisciplinary Natural killer cells PD-1 protein Receptors, Antigen, B-Cell - genetics Science Science (multidisciplinary) Sequence analysis Single-Cell Gene Expression Analysis T-Lymphocytes - cytology T-Lymphocytes - immunology Tumor Burden Tumors
ISSN:	0028-0836, 1476-4687, 1476-4687
Online Access:	Get full text
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Summary:	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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author’s contribution LB and VKK conceived the study. LB with assistance from YCK, JS, AS, SMO, MYVF, DEF, JF, RMB, SZ, SX, designed, performed and analyzed the biological experiments. LB with assistance from YCK, JS, AS, EC, TMD, performed the sequencing experiments, with guidance from AR and ORR. LB, NS,CJG,ZL, FJQ, OA and ETT designed and performed the computational analysis, with guidance from AR. LB, JS, ETT, LA, VKK and AR interpreted the results. JRK and AH S generated and provided the PD-1fl/fl mice. KM and DMR generated and performed the experiments using the CD19Cre/+ x IL-10fl/fl mice. The manuscript was written by LB with assistance from ETT and was edited by LA, AR, and VKK with input from all authors.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-023-06231-0