Sato et al. developed mouse tumorigenic organoid lines that resembled the basal-squamous subtype of the human urothelial carcinoma. In mice implanted with the organoids, anti-PD-1 and anti-CTLA-4 combination (ICB) led to tumor rejection and formation of immunological memory in a manner dependent on CD4+ T cells, but not CD8+ T cells. Tumor rejection did not rely on the expression of MHC class I, MHC class II, or Ifngr1 in the tumor. Mechanistically, ICB expanded IFNγ-producing Th1 CD4+ T cells in the tumor and draining lymph nodes, and IFNγ impaired tumor growth independent of other CD4+ T cell functions.

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-gamma-producing CD4+ T cells. Tumor cells in this system express MHC class I, MHC class II, and the IFN-gamma receptor (Ifngr1), but none were necessary for ICB-induced tumor rejection. IFN-gamma neutralization blocked ICB activity, and, in mice depleted of CD4+ T cells, IFN-gamma 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-gamma effects on the microenvironment.

Author Info: (1) Department of Internal Medicine, Division of Oncology. (2) Department of Internal Medicine, Division of Oncology. (3) McDonnell Genome Institute, and. (4) Department of Internal

Author Info: (1) Department of Internal Medicine, Division of Oncology. (2) Department of Internal Medicine, Division of Oncology. (3) McDonnell Genome Institute, and. (4) Department of Internal Medicine, Division of Oncology. (5) Department of Internal Medicine, Division of Oncology. McDonnell Genome Institute, and. (6) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. (7) Department of Internal Medicine, Division of Oncology.

Less