Immune Predictors of Response after Bacillus Calmette–Guérin Treatment in Non-Muscle-Invasive Bladder Cancer

Abstract

Bacillus Calmette–Guérin (BCG) has been the standard of care for the treatment of high-risk, non-muscle-invasive bladder cancer (NMIBC) for decades, but 49.6% of high-risk and very-high-risk patients will experience progression to muscle-invasive disease in five years. Furthermore, cytology and cystoscopy entail a high burden for both patients and health care systems due to the need for very long periods of follow-up. Subsequent adjuvant treatment using intravesical immunotherapy with BCG has been shown to be effective in reducing tumor recurrence and progression, but it is not free of severe adverse effects that ultimately diminish patients’ quality of life. Because not all patients benefit from BCG treatment, it is of paramount importance to be able to identify responders and non-responders to BCG as soon as possible in order to offer the best available treatment and prevent unnecessary adverse events. The tumor microenvironment (TME), local immune response, and systemic immune response (both adaptive and innate) seem to play an important role in defining responders, although the way they interact remains unclear. A shift towards a proinflammatory immune response in TME is thought to be related to BCG effectiveness. The aim of this review is to collect the most relevant data available regarding BCG’s mechanism of action, its role in modulating innate and adaptive immune responses and the secretion of certain cytokines, and their potential use as immunological markers of response; the aim is also to identify promising lines of investigation.

Breaking Barriers: Modulation of Tumor Microenvironment to Enhance Bacillus Calmette–Guérin Immunotherapy of Bladder Cancer

“…BCG instillation appears to stimulate the expression of PD-L1 in tumor and inflammatory cells through the induction of CD8 + T cells, which are primarily responsible for IFN-γ production [64]. An increase in the number of PD-L1-expressing CD4 + T cells (PD-L1 + Tregs) was reported in BCG-resistant patients [65]. It was also demonstrated that BCG treatment triggers the up-regulation of PD-L1 expression on antigen-presenting cells (APCs), leading to the secretion of certain cytokines such as IL-6 and IL-10, which in turn lead to STAT3 phosphorylation and ultimately PD-L1 expression [66].…”