B Cells and T Follicular Helper Cells Mediate Response to Checkpoint Inhibitors in High Mutation Burden Mouse Models of Breast Cancer.

Abstract

This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.

• Authors: Daniel P Hollern, Nuo Xu, Aatish Thennavan, Cherise Glodowski, Susana Garcia-Recio, Kevin R Mott, Xiaping He, Joseph P Garay, Kelly Carey-Ewend, David Marron, John Ford, Siyao Liu, Sarah C Vick, Miguel Martin, Joel S Parker, Benjamin G Vincent, Jonathan S Serody, Charles M Perou
• Journal: Cell (Cell) Vol. 179 Issue 5 Pg. 1191-1206.e21 (11 14 2019) ISSN: 1097-4172 [Electronic] United States
• PMID: 31730857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• CTLA-4 Antigen
• Immunoglobulin G
• Receptors, Antigen, B-Cell
• Receptors, Antigen, T-Cell

Topics

• Animals
• B-Lymphocytes (immunology)
• CTLA-4 Antigen (metabolism)
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Engineering
• Genome
• Humans
• Immunoglobulin G (metabolism)
• Immunotherapy
• Lymphocyte Activation (immunology)
• Mammary Neoplasms, Animal (genetics, immunology, therapy)
• Mutation (genetics)
• Receptors, Antigen, B-Cell (metabolism)
• Receptors, Antigen, T-Cell (metabolism)
• T-Lymphocytes, Helper-Inducer (immunology)
• Triple Negative Breast Neoplasms (genetics, immunology, pathology, therapy)