TUMOR IMMUNITY

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The interaction between tumor cells and the host immune system are complex, involving a multitude of cell types and mediators. Immune system has the potential to eliminate neoplastic cells, as evidenced by rare but well documented instances of spontaneous remissions (with no or inadequate treatment) in renal cell carcinoma and melanoma.

The development of an immune response requires the highly regulated interaction of a number of different types of white blood cells: CD4+ and CD8+ T cells, NK T cells, neutrophils, macrophages, antibodies (Ab’s), Fc receptors, IFN-γ, and perforin. When exposed to a potential target (antigen), cells called antigen-presenting cells or dendritic cells (DC) take up antigenic material, are activated, and then travel to the lymph nodes. There they interact with T and B lymphocytes, resulting in the generation of antibodies and lymphocyte populations that can kill cells bearing the antigen. In addition to effector populations, regulatory cells that enhance or inhibit the end stage effector response are activate.

Generally speaking there are two broad types of anti-tumor immune responses. One involves the humoral arm of the immune system and the other involves the cellular arm of the immune system. An important aspect of either is the ability of antigen presenting cells to process and present tumor-related peptide antigens that are the primary basis for immune recognition of tumor cells. Tumor antigens that have been phagocytosed and partially digested by antigen presenting cells are presented on the surface of antigen presenting cells, giving the opportunity for the properly sensitized immune system to react to the tumor. Examples of such antigen-presenting cells include macrophages, epidermal Langerhans cells, other types of dendritic cells and B-cells.

The Antibody-Mediated Arm of Tumor Immunity. Antibody-dependent mechanisms of tumor immunity include antibody dependent cell-mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) and opsonization. These mechanisms depend on the ability of the immune system to create antibodies to tumor cell surface.

Antibody-Dependent Cell Medicate Cytotoxicity (ADCC) involves the attachment of tumor-specific antibodies to tumor cells and the subsequent destruction of the tumor cell by immunocompetent cells. Fc receptors on immunocompetent cells recognize the Fc portion of antibodies adhering to surface tumor antigens. Most commonly the effector cell of ADCC is a natural killer (NK) cell. Following recognition and attachment via its Fc receptors, the NK cell can destroy the target tumor cell through release of granules containing perforin and granzymin B and/or activation of apoptosis system in the target cell. Perforin molecules make holes or pores in the cell membrane, disrupting the osmotic barrier and killing the cell via osmotic lysis.

Complement-dependent cell-mediated cytotoxicity (CDC) involves the recognition and attachment of complement-fixing antibodies to tumor specific surface antigens followed by complement activation. Sequential activation of the components of the complement system ultimately lead to the formation of the membrane attack complex (MAC) which forms transmembrane pores that disrupt the osmotic barrier of the membrane and lead to osmotic lysis.

                Opsonization is the process in which tumor-specific antibodies attach to their target antigens on tumor cell surfaces, thus marking them for engulfment by macrophages. This can also lead to processing and presentation of new tumor-specific antigens by the macrophage in addition to direct destruction of the tumor cells.

          The Cell-Medicated Arm of Tumor Immunity. Cell-mediated tumor defenses include cytolytic T-lymphocytes, NK cells and macrophages. Cytolytic (CD8 positive) T-cells recognize the foreign tumor antigens and kill the tumor cell

Interleukins are the generic name given to the intracellular signaling molecules that lymphocytes use to communicate with each other. As such they are important mediators of immunologic responses.

                IL-2 is one of the most important early signaling molecules in an immune response. IL-12 is involved in stimulating the differentiation of helper lymphocytes into Th1 type cells, which are important in cell mediated defense against tumors.

                IFN-g is the interferon. Major roles of IFN-g are to activate macrophages and stimulate antibody production by B-cells. IFN-g has been used as an independent therapy for tumors and as an adjuvant.

Probably there are many proto-tumors that begin to form, taking a few steps along the long route to full-blown cancer, but that are destroyed by the immune system long before they ever become detectable. Probably many more tumors form and take those early steps, and though they are not completely eliminated by the immune system they are controlled — the immune system prevents the proto-tumor from ever becoming more than a little cluster of cells, even though that little cluster of cells may persist for many years.

Actually, that’s not quite what the theory suggests. A tumor that’s reached the detectable level grows faster than the immune system shuts it down, true; but that doesn’t mean there’s no influence of the immune system. Yes, the tumor could be growing twice as fast as it should, with no influence of the immune system. But equally, the tumor could be growing 10 times too fast, with the immune system destroying 90% of that. The overall rate would look the same; but in the latter case, we only need to push the growth rate down, or crank up the immune response, by 11%, to drive the tumor into remission.

On the horizon are anticancer vaccines made by manipulating genes. Intended to protect cancer patients against a recurrence, these vaccines can incorporate genes for immunogenic tumor antigens or genes for histocompatibility antigens able to galvanize killer T cells, as well as genes for substances such as TNF or interleukin-2. Other anticancer strategies call for introducing genes that can shut down cancer-promoting oncogenes or replace faulty cancer-restraining suppressor genes.

Genes can be packaged, for delivery, in a variety of ways: inserted into the genetic material of such carriers as the familiar vaccinia virus (Vaccines Through Biotechnology) or inactivated retroviruses, grafted onto a protein carrier that magnifies the immune response (an adjuvant), or tucked into fat globules known as liposomes.