|Macrophage engulfing |
Despite its long-history of efficacy in the treatment of NMIUC, the mechanism of action of BCG is not well-defined. Subsequently, it is not clear to many patients and practitioners why BCG works. Here we review what is known about the mechanism of action of BCG for NMIUC.
- A competent host immune system is required for BCG to work [3,4]
- Viable BCG is required for a response [5,6]
- More than 40% of patients receiving intravesical BCG instillation experience conversion of a previously negative tuberculin skin test.
- BCG "priming" (exposing a patient to BCG prior to treatment) may improve response rates to intravesical BCG.
- Mice immunized subcutaneously with BCG have improved survival, compared with BCG-naive mice, after intravesical BCG therapy.
- Patients with a pre-existing positive tuberculin skin test have better recurrence-free-survival rates than those without, after intravesical BCG therapy.
MECHANISM OF bcg-mediated immune response IN TREATING BLADDER CANCERThe initial activating step for the inflammatory cascade is binding of BCG to fibronectin (a protein that helps the cell bind molecules) expressed on the urothelium . The BCG is then internalized by both normal urothelial and cancer cells. The host's immune system, through antigen presenting cells (APCs: specifically macrophages and dendritic cells), identifies components of BCG as foreign to the host. Macrophages are the initial line of defense, allowing for cytokine production, BCG antigen presentation, and function in an anti-neoplastic manner against bladder cancer cells . Along with its anti-BCG effects, macrophages also kill cancer cells through direct cell-to-cell contact as well as the release of the cytokines TNF-α and IFN-γ; and the molecule nitric oxide .
Once macrophages and dendritic cells identify components of BCG as foreign, these components are presented as BCG antigens (an antigen is any substance that provokes an immune response) via the MHC (major histocompatibility complex) II leading to a huge immune response. The immune response is mediated through the T-helper (Th) 1 immune response, causing the release of cytokines (proteins used by cells to transmit signals to other cells) that attract more immune cells (neutrophils, lymphocytes, natural killer (NK) cells, macrophages, and dendritic cells) into the wall of the bladder. The Th1 cytokine profile (IFN-γ, IL-2, IL-12) has been demonstrated as necessary for a successful response to BCG; while the alternative Th2 pathway and related cytokines (IL10) are correlated with BCG failure.
Neutrophils are another important cell in the BCG response pathway. Neutrophils become activated and elicit production of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) which specifically targets the malignant bladder cells. A significantly higher level of urinary TRAIL is seen in patients responding to BCG therapy than in non-responders . A systemic immune response is also seen in the form of elevated serum cytokines, cellular and humoral BCG reactivity with in vivo evidence pointing to involvement of CD4+ and CD8+ lymphocytes, NK cells, and granulocytes.[15,16]
|From Luo Y et al. |
This entry was written by Nilay M. Gandhi, MD, senior assistant resident at the Brady Urological Institute at Johns Hopkins.
Some of the data is extracted from the chapter Intravesical Immunotherapy - Bladder Cancer: Diagnosis and Clinical Management by Nilay M. Gandhi, Laura A. Bertrand, Donald L. Lamm, and Michael A. O’Donnell which will appear in newest edition of The Textbook of Bladder Cancer.
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