Jumat, 26 Agustus 2011
Malignant mesothelioma is increasing in incidence and is invariably fatal. Patients commonly present with advanced disease, making treatments, such as surgery and radiotherapy anatomically and technically difficult and often unsuccessful in this group of patients. Furthermore, chemotherapy has historically been ineffective, although in recent years newer regimens with higher response rates have been reported (1–3), but are not curative. Hence, there is a need for new treatments. New therapies, such as immunotherapy and vaccine therapy, therefore, can be readily tested in this disease. Although immunotherapy, vaccine therapy, and combination chemoimmunotherapy separately, these areas are linked and such separations are artificial but necessary.
The Immune Response to a Solid Tumor
To understand how novel therapies might alter the immune response to tumor, it is important to first understand how the immune system responds to cancer under normal circumstances. The antitumor immune response consists of an innate or nonspecific component and an adaptive or specific component. The innate and adaptive immune systems do not act in isolation, each producing soluble factors, such as interferon-g (IFN-g) and interleukins, which may have a stimulatory or inhibitory role for cells from the other arm of the immune response, and there may also be crosstalk between cell populations from the innate and adaptive immune systems, adding further complexity to this interaction. An effective immune response to tumor requires both recognition of tumor by the immune system and the subsequent development of an adequate immune response with the ability to infiltrate the tumor and kill tumor cells. The immune system must recognize tumor antigens; they must be taken up, processed, and presented to CD4+ T cells by dendritic cells, and directly or cross-presented to CD8+ T cells in the context of appropriate co-stimulation. CD8+ T cells must be capable of proliferating, entering the tumor milieu, and then effectively killing tumor or activating other local cells to do so. The magnitude and duration of the cellular response must be adequate to eradicate tumor. Important points in the development of antitumor immunity will be discussed.
The Innate Immune Response
The innate immune system originally evolved to produce a rapid, firstline defense against pathogens. It has not evolved to recognize antigens, and thus has a less important role in antitumor immunity than the adaptive immune system. However, natural killer (NK) cells may have an antitumor role as mediators of antibody-dependent cellular cytotoxicity (ADCC), killing tumor cells coated with antibody via their receptor for immunoglobulin G (IgG). Furthermore, they interact with the adaptive immune system by secreting IFN-g and other cytokines, such as interleukin-1 (IL-1) and granulocyte-macrophage colonystimulating factor (GM-CSF) when activated. They may also have a role in surveillance against malignant transformation. Neutrophils play an important role in acute inflammation and the immediate response against infection, but their role in antitumor immunity has received little attention, despite the fact that neutrophil infiltration of tumors corresponds with a favorable prognosis in some studies, and that most cytokine treatments of experimental tumors show a strong neutrophil infiltrate in responding sites (4). Once recruited into the tumor, neutrophils can produce IL-1b, tumor necrosis factor-a (TNF-a), and interferons, and can also kill tumor cells by ADCC (5). Tumor macrophages infiltrates are often heavy, and these cells may have a role in antigen presentation and tumor cytotoxicity, e.g., via production of nitrous oxide (NO).
