Back to Search
Start Over
CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade
- Source :
- JCI Insight. 3
- Publication Year :
- 2018
- Publisher :
- American Society for Clinical Investigation, 2018.
-
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.
- Subjects :
- CD4-Positive T-Lymphocytes
Male
0301 basic medicine
medicine.medical_treatment
CD8-Positive T-Lymphocytes
Interferon-gamma
Mice
03 medical and health sciences
Antigen
Cancer immunotherapy
Antigens, Neoplasm
Interferon
Neoplasms
MHC class I
Tumor Microenvironment
medicine
Animals
Humans
Antibodies, Blocking
Receptors, Interferon
Mice, Knockout
MHC class II
Tumor microenvironment
biology
Chemistry
Histocompatibility Antigens Class I
Histocompatibility Antigens Class II
Neoplasms, Experimental
General Medicine
Immune checkpoint
Mice, Inbred C57BL
030104 developmental biology
Urinary Bladder Neoplasms
biology.protein
Cancer research
Immunotherapy
Lymph Nodes
Urothelium
Neoplasm Transplantation
CD8
Research Article
medicine.drug
Subjects
Details
- ISSN :
- 23793708
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....dfa2382b5f6e4f352d7a82f74df07a9e