Role of urothelial cells in BCG immunotherapy for superficial bladder cancer

Abstract

Intravesical instillation of Bacillus Calmette-Guérin (BCG) is used for the treatment of superficial bladder cancer, both to reduce the recurrence rate of bladder tumour and to diminish the risk of progression. Since its first therapeutic application in 1976, major research efforts have been directed to decipher the exact mechanism of action of the BCG-associated antitumour effect. Bacillus Calmette-Guérin causes an extensive local inflammatory reaction in the bladder wall. Of this, the massive appearance of cytokines in the urine of BCG-treated patients stands out. Activated lymphocytes and macrophages are the most likely sources of these cytokines, but at present other cellular sources such as urothelial tumour cells cannot be ruled out. Bacillus Calmette-Guérin is internalised and processed both by professional antigen-presenting cells and urothelial tumour cells, resulting in an altered gene expression of these cells that accumulates in the presentation of BCG antigens and secretion of particular cytokines.

Figure 1

Simplified scheme of the supposed mechanism of action of BCG in tumour cell eradication. After its instillation in the bladder (A), BCG (B) accumulates near the bladder wall, followed by adherence and passage through the GAG layer of the bladder wall (C). Bacillus Calmette-Guérin is internalised and processed by professional antigen-presenting cells (APCs) and (high-grade) tumour cells (D), and BCG antigens are presented to CD4⁺ T cells (E). Depending on various conditions, this results in the local synthesis of a particular set of cytokines, known as the Th1-type or cell-mediated immune response (F, G). The Th1 cytokine profile enables recruitment and maturation of cytotoxic effector cells. No definite statements can be made yet about the actual effector cell(s), but a key role for NK cells in tumour cell killing has been proposed (H).