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CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade
Yuji Sato, … , Jennifer K. Sehn, Vivek K. Arora
Yuji Sato, … , Jennifer K. Sehn, Vivek K. Arora
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e121062. https://doi.org/10.1172/jci.insight.121062.
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Research Article Immunology Oncology

CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade

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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

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Figure 1

MCB6C is a transplantable organoid model of urothelial carcinoma, with features of human basal-squamous urothelial carcinoma.

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MCB6C is a transplantable organoid model of urothelial carcinoma, with f...
(A) Schematic representation of how the MCB6 organoid lines were established from a BBN-treated mouse. Images (original magnification, ×10) were obtained with NanoZoomer-XR. Scale bar: 200 μM. (B) Histologic and immunohistochemical evaluation of a s.c. MCB6C tumor collected 28 days after injection of organoid cells. A normal mouse bladder (NMB) specimen was used as positive control for UPKIII staining. Scale bar: 200 μM.

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