ABSTRACT
Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.
Subject(s)
Non-Muscle Invasive Bladder Neoplasms , Urinary Bladder Neoplasms , Humans , Adjuvants, Immunologic/therapeutic use , BCG Vaccine/therapeutic use , Immunotherapy , Administration, Intravesical , Urinary Bladder Neoplasms/drug therapy , Biology , Neoplasm Invasiveness , Neoplasm Recurrence, Local/drug therapyABSTRACT
Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease that is expressed constitutively by many haematopoietic and non-haematopoietic tissues. It exists as a membrane-associated protein, as well as in an active, soluble form (herein called sDPP4), present at high concentrations in bodily fluids. Despite the proposed use of sDPP4 as a biomarker for multiple diseases, its cellular sources are not well defined. Here, we report that individuals with congenital lymphocyte immunodeficiency had markedly lower serum concentrations of sDPP4, which were restored upon successful treatment and restoration of lymphocyte haematopoiesis. Using irradiated lymphopenic mice and wild-type to Dpp4-/- reciprocal bone marrow chimeric animals, we found that haematopoietic cells were a major source of circulating sDPP4. Furthermore, activation of human and mouse T lymphocytes resulted in increased sDPP4, providing a mechanistic link between immune system activation and sDPP4 concentration. Finally, we observed that acute viral infection induced a transient increase in sDPP4, which correlated with the expansion of antigen-specific CD8+ T cell responses. Our study demonstrates that sDPP4 concentrations are determined by the frequency and activation state of lymphocyte populations. Insights from these studies will support the use of sDPP4 concentration as a biomarker for inflammatory and infectious diseases.
Subject(s)
Biomarkers/metabolism , Dipeptidyl Peptidase 4/metabolism , Influenza A virus/physiology , Membrane Proteins/metabolism , Orthomyxoviridae Infections/immunology , Severe Combined Immunodeficiency/immunology , T-Lymphocytes/immunology , Animals , Bodily Secretions , Dipeptidyl Peptidase 4/genetics , Disease Models, Animal , Hematopoiesis/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Solubility , Transplantation ChimeraABSTRACT
The pathogenesis of urinary tract infection and mechanisms of the protective effect of Bacillus Calmette-Guerin (BCG) therapy for bladder cancer highlight the importance of studying the bladder as a unique mucosal surface. Innate responses to bacteria are reviewed, and although our collective knowledge remains incomplete, we discuss how adaptive immunity may be generated following bacterial challenge in the bladder microenvironment. Interestingly, the widely held belief that the bladder is sterile has been challenged recently, indicating the need for further study of the impact of commensal microorganisms on the immune response to uropathogen infection or intentional instillation of BCG. This review addresses the aspects of bladder biology that have been well explored and defines what still must be discovered about the immunobiology of this understudied organ.
