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

Lloyd Bod, Yoon-Chul Kye, Jingwen Shi, Elena Torlai Triglia, Alexandra Schnell, Johannes Fessler, Stephen M. Ostrowski, Max Y. Von-Franque, Juhi R. Kuchroo, Rocky M. Barilla, Sarah Zaghouani, Elena Christian, Toni Marie Delorey, Kanishka Mohib, Sheng Xiao, Nadine Slingerland, Christopher J. Giuliano, Orr Ashenberg, Zhaorong Li, David M. Rothstein, David E. Fisher, Orit Rozenblatt-Rosen, Arlene H. Sharpe, Francisco J. Quintana, Lionel Apetoh, Aviv Regev () and Vijay K. Kuchroo ()
Additional contact information
Lloyd Bod: Harvard Medical School and Brigham and Women’s Hospital
Yoon-Chul Kye: Harvard Medical School and Brigham and Women’s Hospital
Jingwen Shi: Harvard Medical School and Brigham and Women’s Hospital
Elena Torlai Triglia: Broad Institute of MIT and Harvard
Alexandra Schnell: Harvard Medical School and Brigham and Women’s Hospital
Johannes Fessler: Harvard Medical School and Brigham and Women’s Hospital
Stephen M. Ostrowski: Massachusetts General Hospital
Max Y. Von-Franque: Massachusetts General Hospital
Juhi R. Kuchroo: Harvard Medical School and Brigham and Women’s Hospital
Rocky M. Barilla: Harvard Medical School and Brigham and Women’s Hospital
Sarah Zaghouani: Harvard Medical School and Brigham and Women’s Hospital
Elena Christian: Broad Institute of MIT and Harvard
Toni Marie Delorey: Broad Institute of MIT and Harvard
Kanishka Mohib: University of Pittsburgh School of Medicine
Sheng Xiao: Harvard Medical School and Brigham and Women’s Hospital
Nadine Slingerland: Harvard Medical School and Brigham and Women’s Hospital
Christopher J. Giuliano: Broad Institute of MIT and Harvard
Orr Ashenberg: Broad Institute of MIT and Harvard
Zhaorong Li: Brigham and Women’s Hospital, Harvard Medical School
David M. Rothstein: University of Pittsburgh School of Medicine
David E. Fisher: Massachusetts General Hospital
Orit Rozenblatt-Rosen: Broad Institute of MIT and Harvard
Arlene H. Sharpe: Harvard Medical School and Brigham and Women’s Hospital
Francisco J. Quintana: Broad Institute of MIT and Harvard
Lionel Apetoh: Harvard Medical School and Brigham and Women’s Hospital
Aviv Regev: Broad Institute of MIT and Harvard
Vijay K. Kuchroo: Harvard Medical School and Brigham and Women’s Hospital

Nature, 2023, vol. 619, issue 7969, 348-356

Abstract: 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 growth1,2. 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.

Date: 2023
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DOI: 10.1038/s41586-023-06231-0

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