NK cells are essential for effective BCG immunotherapy

Abstract

Adjuvant intravesical bacillus Calmette‐Guérin (BCG) therapy is a well‐established and successful adjuvant immunotherapy in the treatment of superficial bladder cancer. Although the function of natural killer (NK) cells in other immunotherapeutic regimens (e.g., lymphokine‐activated killer [LAK] cell or interleukin‐2 [IL‐2] therapy) has been established, the contribution of NK cells to effective BCG immunotherapy is not clear. We used a human in vitro system to analyze the role of NK cells in BCG‐induced cellular cytotoxicity. After stimulation of mononuclear cells with BCG for 7 days, these BCG‐activated killer (BAK) cells displayed substantial cytotoxicity against bladder tumor cells. Magnetic depletion experiments and fluorescence activated cell sorting revealed that NK cells were the major effector cell population. To address NK cell function in vivo, we studied a syngeneic orthotopic murine bladder cancer model and compared BCG immunotherapy in C57BL/6 wild‐type mice, NK‐deficient beige mice and mice treated with anti‐NK1.1 monoclonal antibody. Four weekly instillations of viable BCG significantly prolonged survival in wild‐type mice compared with control mice treated with solvent alone. In contrast, BCG therapy was completely ineffective in NK‐deficient beige mice and in mice treated with anti‐NK1.1 monoclonal antibody. These findings suggest a key role for NK cells during BCG immunotherapy. © 2001 Wiley‐Liss, Inc.

Role of urothelial cells in BCG immunotherapy for superficial bladder cancer

“…Furthermore, Il-6 seems to contribute to MHC-nonrestricted cytotoxic activity by inducing natural killer (NK) cell proliferation. Nowadays, NK cells are considered as essential, cytotoxic effector cells during BCG therapy ( Figure 1H) (Brandau et al, 2001).…”

“…A key role is supposed for NK cells (Brandau et al, 2001). NK cells, a special population of mononuclear cells, recognise 'self'-peptides presented by MHC class I molecules on the surface of cells.…”

“…This may be a trigger for NK cells to attack BCG-infected urothelial tumour cells. Bacillus Calmette-Guérin therapy in the murine model, using NK celldeficient mice, is ineffective (Brandau et al, 2001). However, in studies regarding the presence of NK cells after BCG therapy, relatively few NK cells were seen 3 weeks after the last instillation of a 6-week course (Lattime et al, 1992;Saint et al, 2001).…”

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

“…Effective BCG therapy requires induction of a T-cell-mediated immune response (Ratliff et al, 1987;Ratliff, 1992) and the activation of a natural killer (NK) cell-like population with an apparent ability to distinguish between normal and cancer cells (Bohle et al, 1993;Brandau et al, 2001). Significantly, both T-celland NK-cell-deficient mice respond poorly to BCG therapy (Brandau et al, 2001).…”

“…Significantly, both T-celland NK-cell-deficient mice respond poorly to BCG therapy (Brandau et al, 2001). Following BCG instillation, it has been shown that there is an accumulation of immunocompetent cells into the bladder wall including activated T helper (Th) lymphocytes, NK cells and DCs; adhesion molecules (ICAMs) and costimulatory B7 antigens are also upregulated (Patard et al, 1996;Saint et al, 2001).…”