This project aims to address the high rates of recurrence and progression following treatment of non-muscle invasive bladder cancer (NMIBC). There is a need for accurate biomarkers to predict response to the gold standard therapy for NMIBC, Bacillus Calmette-Guérin (BCG). An increased ability to predict patient response to BCG therapy would lead to overall improvement in recurrence and survival rates for bladder cancer. External validation of predictive biomarkers identified would allow for implementation on a larger scale.

While intravesical instillation with Bacillus Calmette-Guérin (BCG) is the gold standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC), disease recurrence and progression occur frequently. When NMIBC patients do not respond to BCG, treatment options are limited. Thus, there is a need of biomarkers that can accurately predict response. Based on a cohort of 33 patients with high- or intermediate-risk NMIBC we demonstrated that trained immunity (TI) acquired by peripheral blood monocytes, following induction BCG therapy, is associated with recurrence-free survival and may thus serve as a biomarker of response to BCG. TI involves epigenetic reprogramming leading to acquisition of long-lasting memory in innate immune cells following exposure to inflammatory stimuli such as BCG. TI may also function as a therapeutic target, as we have mechanistic evidence linking BCG-induced TI to improved anti-tumour responses. Using a mouse model of NMIBC, we showed that TI contributes to the remodelling of the tumor microenvironment, as co-instillation of BCG-trained macrophages with bladder tumor cells increased the proportion of tumor-specific cytotoxic T lymphocytes. We also showed that, compared with intravesical immunotherapy, activation of systemic immunity after intravenous BCG resulted in an enhanced anti-tumor immune microenvironment in the bladder and peripheral lymphoid organs. Our data support the concept that systemic immune activation following BCG therapy promotes anti-tumor responses, and that peripherally acquired TI is important in driving anti-tumor responses necessary for therapeutic benefit. Characterizing mechanisms of BCG-mediated systemic immune activation may lead to elucidation of more accurate biomarkers of response and novel therapeutic modalities resulting in better patient outcomes.

Graham CH, Paré JF, Cotechini T, Hopman W, Hindmarch C, Ghaffari A, et al. Innate immune memory is associated with increased disease-free survival in bladder cancer patients treated with bacillus Calmette-Guérin. Canadian Urological Association Journal. 2021; 15:E412. 10.5489/cuaj.7066.

Paré JF, Tabasinezhad M, Grossman A, Atallah A, Hindmarch C, Tyryshkin K, et al. Association of Histone H3 Trimethylation in Circulating Monocytes with Lack of Early Recurrence in Patients with Bladder Cancer following BCG Induction Therapy. Bladder Cancer. 2023; 9:175-186. 10.3233/BLC-230028.