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

• Published in: Cell Vol. 179; no. 5; pp. 1191 - 1206.e21
• Main Authors: Hollern, Daniel P., Xu, Nuo, Thennavan, Aatish, Glodowski, Cherise, Garcia-Recio, Susana, Mott, Kevin R., He, Xiaping, Garay, Joseph P., Carey-Ewend, Kelly, Marron, David, Ford, John, Liu, Siyao, Vick, Sarah C., Martin, Miguel, Parker, Joel S., Vincent, Benjamin G., Serody, Jonathan S., Perou, Charles M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.11.2019
• Subjects: Animals; B cells; B-Lymphocytes - immunology; breast cancer; CTLA-4 Antigen - metabolism; CTLA4; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Genetic Engineering; Genome; genomics; Humans; immune checkpoints; Immunoglobulin G - metabolism; Immunotherapy; Lymphocyte Activation - immunology; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - immunology; Mammary Neoplasms, Animal - therapy; mouse models; Mutation - genetics; PD1; Receptors, Antigen, B-Cell - metabolism; Receptors, Antigen, T-Cell - metabolism; T cells; T-Lymphocytes, Helper-Inducer - immunology; TMB; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - therapy; tumor mutation burden; mouse models; tumor mutation burden; immunotherapy; TMB; breast cancer; genomics; CTLA4; B cells; PD1; T cells; immune checkpoints
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.10.028

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. [Display omitted] •New TNBC murine models with high mutation burden and immune cell activity•A genomics resource of immune checkpoint treated tumors from TNBC murine models•Immune checkpoint blockade activates Tfh and B cells in the anti-tumor response•B cells impact immunotherapy response by secreting antibody and activating T cells Mouse models of triple-negative breast cancer provide insights into how T follicular helper cell activation of B cells facilitates the effects of immune checkpoint inhibitors.