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

2019; Cell Press; Volume: 179; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2019.10.028

1097-4172

Daniel P. Hollern, Nuo Xu, Aatish Thennavan, Cherise Ryan Glodowski, Susana García‐Recio, Kevin R. Mott, Xiaping He, Joseph P. Garay, Kelly Carey-Ewend, David Marron, John Ford, Siyao Liu, Sarah C. Vick, Miguel Martín, Joel S. Parker, Benjamin G. Vincent, Jonathan S. Serody, Charles M. Perou,

CAR-T cell therapy research

Summary 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.