Innate immune memory is associated with increased disease-free survival in bladder cancer patients treated with bacillus Calmette-Guérin

Abstract

Introduction: While studies suggest that innate immune memory acquired by circulating monocytes may mediate the benefit of bacillus Calmette-Guérin (BCG) in the treatment of patients with high-risk non-muscle-invasive bladder cancer (NMIBC), prospective studies are lacking. Innate immune memory is defined by enhanced release of pro-inflammatory cytokines by innate immune cells following a secondary challenge with pattern recognition receptor (PRR) ligands.
 Methods: Peripheral blood monocytes isolated from 33 patients with intermediate- or high-risk NMIBC before and after two or five induction BCG instillations were stimulated with the PRR ligand lipopolysaccharide (LPS). Inflammatory cytokine levels in the culture medium were measured. Extent of innate immune memory acquisition was determined by dividing the levels of cytokines released after BCG instillation by the levels released prior to BCG therapy.
 Results: Monocytes secreted variable levels of TNFα, IL-1β, IL-6, IFNγ, IL-12, and IL-10. Compared with patients with recurrences, the post-BCG:pre-BCG ratio of IL-12 in monocyte cultures from patients without recurrences after five BCG instillations was significantly increased. Patients with no innate immune memory (based on IL-12 ratios) had significantly shorter times-to-recurrence than patients with innate immune memory (p<0.001). Eighty-four percent (16/19) of patients with innate immune memory vs. only 22% (2/9) of patients without memory had disease-free survival of over 500 days.
 Conclusion: Results demonstrate a potential link between BCG-induced innate immune memory peripherally and local anti-tumor responses. Further validation will increase our understanding of the mode of action of BCG and, therefore, will be used to enhance its effectiveness.

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

“… 46 Graham et al described variable post-BCG versus pre-BCG ratios of cytokines released by monocytes following LPS stimulation in 33 NMIBC patients during BCG induction, with approximately half of the patients showing an increase in ratios. 95 A limitation of all these studies is that they only assessed the cytokine production during a BCG induction cycle which may be influenced by the immunological processes of priming or tolerance. 68 …”

Immune profiles and DNA methylation alterations related with non-muscle-invasive bladder cancer outcomes

“…Previous studies have shown that tumor immune environments may interact with BCG and interfere with the efficacy of this therapy. For instance, IL-12 secreted by BCG-induced monocytes was increased in NMIBC patients without tumor recurrence, a phenomenon that may involve the innate immune memory of circulating monocytes [ 45 ]. Nevertheless, patients receiving BCG in our study did not have peripheral immune cell profiles that differed from patients who were BCG naïve, and BCG was not significantly associated with NMIBC outcomes.…”

BCG in Bladder Cancer Immunotherapy

“…Monocytes isolated from patients with bladder cancer after intravesical BCG demonstrated enhanced cytokine responses to ex vivo stimulation with lipopolysaccharide (LPS) compared to monocytes from the same patients before BCG treatment was initiated, suggesting that these monocytes had undergone immune training [67]. Furthermore, increased secretion of IL-12 by monocytes stimulated ex vivo with LPS after completion of five weekly instillations of BCG as compared to before BCG initiation was found to correlate with favorable clinical responses [68]. Further studies are ongoing to clarify the role of trained immunity in BCG treatment of bladder cancer.…”