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Citation Information: JCI Insight. 2018;3(23):e121062. https://doi.org/10.1172/jci.insight.121062.
Abstract
Immune checkpoint blockade (ICB) provides clinical benefit to a minority of patients with urothelial carcinoma (UC). The role of CD4+ T cells in ICB-induced antitumor activity is not well defined; however, CD4+ T cells are speculated to play a supportive role in the development of CD8+ T cells that kill tumor cells after recognition of tumor antigens presented by MHC class I. To investigate the mechanisms of ICB-induced activity against UC, we developed mouse organoid-based transplantable models that have histologic and genetic similarity to human bladder cancer. We found that ICB can induce tumor rejection and protective immunity with these systems in a manner dependent on CD4+ T cells but not reliant on CD8+ T cells. Evaluation of tumor infiltrates and draining lymph nodes after ICB revealed expansion of IFN-γ–producing CD4+ T cells. Tumor cells in this system express MHC class I, MHC class II, and the IFN-γ receptor (Ifngr1), but none were necessary for ICB-induced tumor rejection. IFN-γ neutralization blocked ICB activity, and, in mice depleted of CD4+ T cells, IFN-γ ectopically expressed in the tumor microenvironment was sufficient to inhibit growth of tumors in which the epithelial compartment lacked Ifngr1. Our findings suggest unappreciated CD4+ T cell–dependent mechanisms of ICB activity, principally mediated through IFN-γ effects on the microenvironment.
Authors
Yuji Sato, Jennifer K. Bolzenius, Abdallah M. Eteleeb, Xinming Su, Christopher A. Maher, Jennifer K. Sehn, Vivek K. Arora
Usage data is cumulative from December 2018 through December 2019.
| Usage | JCI | PMC |
|---|---|---|
| Text version | 2,305 | 0 |
| 442 | 0 | |
| Figure | 447 | 0 |
| Table | 44 | 0 |
| Supplemental data | 100 | 0 |
| Citation downloads | 37 | 0 |
| Totals | 3,375 | 0 |
| Total Views | 3,375 | |
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