Tumors Evading Detection!!!!! Melanoma.. Jim Breitfeller

Tumors Evading Detection
Lack of costimulation:

Many Melanoma tumor cells do not have the B7 protein on their surface so this co-stimulatory second signal cannot take place. Theoretically, they should cause an immune response but they do not stimulate an effective anti-tumor immune response. The first signal originates from the binding of the T cell receptor (TCR) to its antigen-MHC, and provides the specificity of the interaction. Without this signal, the cell enters anergic state and can act as a T reg cell. Expression of B7 on the surface of a cell is the costimulatory signal necessary to allow for the cytolytic CD8+ T cell attack on the tumor. B7 display renders tumor cells capable of effective antigen presentation, leading to their eventual eradication.

Secretion of immunosuppressive cytokines:

Another way tumors evade detection is by secretion of certain cytokines. They are low-molecular weight proteins that use their communication ability to regulate the immune response. Cytokines can act upon either the cells secreting them (autocrine) or on neighboring cells (paracrine) to generate activities in the targeted cells. This means they can act as light switches for on and off immune responses. For example, interleukin-2 activates a cell-mediated immune response, while interleukin-10 suppresses cell-mediated responses. Many types of cancer, including Melanoma, take advantage of this ability to down regulate this appropriate immune response to help extend their survival and proliferation. This causes cancer patients to fail in mounting a successful attack on the tumors. Immunosuppressive cytokines secreted by cancer cells include transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF).

TGF-beta is one of the most potent immunosuppressive cytokines characterized to date. It is capable of affecting the proliferation, activation and differentiation of cells participating in both the innate and acquired immune response.TGF-beta inhibits the profilation T-cells, B cells, Natural killer cells (NK), and macrophages.TGF-beta also converts T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction. Another of TGF-beta's affect is on cytotoxic T lymphocytes (CTLs) This is very important for anti-tumor immunity because of their cytotoxic effects. TGF-beta down-regulates many of the processes necessary for CTL activation. Without this activation, there is no assault on the tumor cells from the CTLs. In addition to suppressing proliferation, TGF-beta has been shown to induce apoptosis (cell death) in B and T cells.

Another immunosuppressive cytokine is IL-10. It is capable of inhibiting the prodction of of pro-inflammatory cytokines like IFN-gamma, IL-2, and GM-CSF made by cells such as macrophages and T helper cells. IL-10 also displays potent abilities to suppress the antigen presentation capacity of antigen presenting cells. Secretion of IL-10 in the vicinity of a tumor can render the tumor totally insensitive to CTL-mediated lysis. It is most likely that the tumor’s microenvironment is altered enough to block or turn off the discharge granules that would lyses the tumor cell. However, it is also stimulatory towards certain T cells, mast cells and B cells. It enhances B cell survival, proliferation, and antibody production. As you can see, IL-10 has many rolls to play when it come to the immune system.

The cytokine VEGF is produced by most tumors.
Vascular endothelial growth factor (VEGF) is a cytokine that is produced by most tumors. This growth factor enables the tumor to expand vascularly when is in its growth phase. VEGF production can be induced in tumor cells that are not receiving enough oxygen.

Regulatory T-cells (Tregs) (suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens.1

Tumor Growth kinetics

The cell cycle has four stages:

1. G1 phase when the cell increases in size and gets ready to replicate its DNA.
2. S phase when the cell synthesizes or copies its chromosomes
3. G2 phase in which the cell prepares to divide
4. M phase when mitosis occurs.

When the various growth inhibitory proteins and checkpoint controls which regulate this cycle become disabled due to mutations characteristic of cancerous cells, the cell cycle is no longer under tight regulation. Tumor cells are capable of proliferating so quickly that the immune response is not fast enough to keep their growth in check. The growth of the tumor cells outpaces the immune response and escape the detection of the immune system. Lack of cell cycle controls leads to excessive proliferation of tumor cells.





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Take care

Jimmy B