Hollern et al. used UV radiation or cytidine deaminase (apobec3) gene overexpression to mutate triple-negative mouse GEMM mammary tumors. Response to immune checkpoint inhibition (ICI) was predicted by high tumor mutation burden, and mRNAseq of pretreatment samples revealed correlations with immune cell/activity genes (also noted in pretreatment samples from ICI-responsive patients with breast and melanoma tumors). Flow cytometry, IHC, and scRNAseq of tumor-bearing mice showed ICI response relied on Treg inhibition and T follicular helper cell stimulation of B cells to make antibodies and activate effector memory T cells.
Contributed by Paula Hochman
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.