Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections

Abstract

BackgroundBCG is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity.MethodsThe aim of this research was to determine whether BCG immunotherapy induces trained immunity in NMIBC patients. We conducted a prospective observational cohort study in 17 NMIBC patients scheduled for BCG therapy and measured trained immunity parameters at 9 time points before and during a 1-year BCG maintenance regimen. Ex vivo cytokine production by peripheral blood mononuclear cells, epigenetic modifications, and changes in the monocyte transcriptome were measured. The frequency of respiratory infections was investigated in two larger cohorts of BCG-treated and non-BCG treated NMIBC patients as a surrogate measurement of trained immunity. Gene-based association analysis of genetic variants in candidate trained immunity genes and their association with recurrence-free survival and progression-free survival after BCG therapy was performed to investigate the hypothesized link between trained immunity and clinical response.ResultsWe found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1β after heterologous ex vivo stimulation of circulating monocytes 6–12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40 to 1.01)) for respiratory infections in BCG-treated versus non-BCG-treated NMIBC patients. An epigenomics approach combining chromatin immuno precipitation-sequencing and RNA-sequencing with in vitro trained immunity experiments identified enhanced inflammasome activity in BCG-treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC.ConclusionWe conclude that BCG immunotherapy induces trained immunity in NMIBC patients and this may account for the protective effects against respiratory infections. The data of our gene-based association analysis suggest that a link between trained immunity and oncological outcome may exist. Future studies should further investigate how trained immunity affects the antitumor immune responses in BCG-treated NMIBC patients

Response to 2 Induction Courses of Bacillus Calmette-Guèrin Therapy Among Patients With High-Risk Non–Muscle-Invasive Bladder Cancer

“…Patients with preexisting BCG-specific immunity, as measured by a positive purified protein derivative (PPD) skin test, or BCG-specific T cells, have longer RFS, suggesting that initially priming local immunity may improve BCG therapy response. A robust local and systemic immune response associated with long-term systemic trained immunity can be achieved with intravesical BCG instillation alone, and these studies suggest that first exposure to BCG primes the immune system to enhance the antitumor effect of a second exposure. The forthcoming SWOG S1602 results are anticipated to deepen our understanding of BCG priming.…”

Vaccination with intravenous BCG protects macaques with pre-existing SIV infection from tuberculosis

“…Furthermore, these responses were maintained despite antimycobacterial drug treatment initiated by 4 weeks after administration of IV BCG. BCG has been shown to enhance innate immunity against TB through epigenetic modifications of hematopoietic stem cells, referred to as trained immunity [43][44][45][46] . Although this was not investigated in the current study, trained immunity in the context of pre-existing SIV and BCG vaccination will be a focus in future studies.…”

The potency of hematopoietic stem cell reprogramming for changing immune tone

“…52 The intra-bladder administration of BCG induces hyperactive monocytes, and patients who received intra-bladder BCG had a decreased rate of upper respiratory infections indicative of the induction of general trained immunity in these patients. 53 While BCG administered via other routes (intradermally for the TB vaccine and intravenously in animal models) can induced systemic reprogramming of hematopoiesis 24,54,55 it has been unclear if its use in the bladder and as a cancer microbial immunotherapy are via local bladder epithelial effects or systemic and hematopoietic reprogramming, and if the later, what the relevance of BCG immunotherapy might be of diverse other tumors. 50 We aimed to address the anti-tumor mechanisms induced by intra-bladder BCG and we have now demonstrated that bladder administration of BCG induces epigenetic and transcriptional changes in HSPC in mouse and human.…”