Infiltrating Natural Killer cells influence the efficacy of BCG immunotherapy in non-muscle-invasive bladder cancer

Non-muscle-invasive bladder cancer (NMIBC) consists of tumors restricted to the bladder urothelium or lamina propria, without invasion of the muscular layer. Intravesical BCG (Bacillus Calmette-Guérin) is widely used as an adjuvant therapy for patients with intermediate or high-risk NMIBC. However, a significant proportion of these patients fail to respond to BCG or recur after treatment. Moreover, despite decades of BCG usage, there are still no clinically validated biomarkers capable of predicting which patients will benefit from this treatment. Emerging evidence suggests that the tumor immune microenvironment influences the efficacy of BCG immunotherapy. In this context, our study aimed to assess, by immunohistochemistry, whether the abundance of immune cell subpopulations – Natural Killer (NK) cells, tumor-associated macrophages (TAMs), CD4 + T, CD8 + T, and FOXP3 + regulatory T (Treg) cells, or T cell ratios (CD4 +/CD8 + and FOXP3 +/CD8 +) – in NMIBC urothelium, prior to BCG, were associated with BCG response rate (RR) and recurrence-free survival (RFS) after treatment. We demonstrated that higher pretreatment NK cell count in the NMIBC urothelium is significantly associated with improved BCG RR and prolonged RFS after BCG immunotherapy. We hypothesize these results are associated with BCG-induced trained immunity, which has been proposed to be essential for the efficacy of BCG immunotherapy in bladder cancer. Once validated and further investigated by future studies, our findings may help to improve the stratification and treatment of patients with NMIBC.