美国北卡罗来纳大学Charles M. Perou研究组提出，在高突变负荷的乳腺癌小鼠模型中，B细胞和滤泡辅助T细胞介导对检查点抑制剂的应答。该项研究成果发表在2019年11月14日出版的《细胞》上。

通过建立新的乳腺肿瘤模型，研究人员发现肿瘤突变负荷和特定免疫细胞的反应相关。此外，研究人员从敏感和耐药的小鼠模型中，获得了经过免疫治疗和未治疗的肿瘤丰富的单细胞RNA-seq和大量mRNA-seq数据。使用这种方法，研究人员发现免疫检查点疗法可诱导B细胞的滤泡辅助性T细胞活化，从而促进这些模型中小鼠的抗肿瘤反应。研究人员还发现，T细胞的B细胞活化和抗体的产生是免疫疗法反应的关键，并为免疫检查点疗法提供了新的生物标记物。总的来说，这项工作建立了乳腺癌临床前新模型，并提供了针对治疗敏感个体的mRNA-seq和单细胞RNA-seq数据库，还揭示了应对免疫检查点抑制剂反应的新成分。

据悉，这项研究使用三阴性乳腺癌小鼠模型确定了介导免疫检查点抑制剂反应的机制。

附：英文原文

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

Author: 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

Issue&Volume: 2019/11/14

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.

DOI: 10.1016/j.cell.2019.10.028

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31178-X