Effect of Systemic Versus Localized Bacillus Calmette-Guérin Immunotherapy on Bladder Cancer Progression: Novel Role for Trained Immunity

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Atallah, Aline
Cancer Immunology , Bladder Cancer , Systemic Immunity , Trained Immunity , Bacillus Calmette-Guerin
The standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG). Unfortunately, most patients do not respond fully to this therapy, and our understanding of the immunotherapeutic effect of BCG is incomplete. The tumor immune microenvironment (TiME) is known to influence responses to immunotherapy, and there is mounting evidence that the activation of a systemic immune response is critical for the induction of local anti-tumour responses. Based on this knowledge, we hypothesized that compared with the standard intravesical route, systemic intravenous administration of BCG will result in improved anti-tumour immune responses. Using a syngeneic orthotopic mouse model of NMIBC, here we show that bladder tumors from mice that received intravenous BCG treatment were smaller compared with those that received intravesical BCG treatment. This reduction in tumor size was associated with an increased proportion of CD8+ T cells, with a skew towards tumour-specific T cells, and a reduced proportion of inflammatory and patrolling monocytes in bladder tumors. Our results also indicate that, in the absence of a tumour, intravesical BCG treatment leads to increased proportion of neutrophils in the bladder, which have been associated with a tumour-permissive niche. Furthermore, we investigated the role of trained immunity, also known as innate immune memory, as a potential mechanism through which BCG-induced systemic immunity leads to local anti-tumour effects. Our study indicates that co-instillations of cancer cells and BCG-trained macrophages lead to a more cancer-specific CD8+ T cells phenotype compared with untrained macrophages. Together, our results demonstrate that systemic immunity is required for optimal anti-tumour responses and that BCG-induced trained immunity represents a potential mechanism by which systemic immunity induces local responses. Understanding the link between systemic immunity, trained immunity, and the TiME following BCG therapy may facilitate the development of new approaches to improve outcomes and reduce recurrence rates in patients with NMIBC.
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