IMMUNE RESPONSE TO MALIGNANCIES

ABSTRACT
When immune cells and developing tumor cells localize to a common microenvironment, an assemblage of interaction takes place. This results in either tumor destruction by way of immunosurveillance or tumor outgrowth.
Immune response to tumor associated antigens exist in tumor bearing hosts but are usually not successful in eliminating malignant cells or preventing the development of metastases.
Tumors are genetically unstable, and the emergences of genetic variants ensures that the tumor survives in the face of the host immune system. It is likely that tumor cells recognized by the immune system are eliminated as they arise, and only those tumor cells that manage to foil the immune surveillance escape and survive.
However, another studies suggest that the immune system can also actively promote formation on certain tumors. These apparent disparate effects of immunity on tumorigenesis provide a unique model for study of the decision-making process that dictates immune function within a tumor.
In this review, we will discuss the concepts that the panoply of immune system-tumor cell interactions that have been reported are non-mutually exclusive combinations of various positive and negative forces in action, with the protective actions of immunity being the best possible result and the tumor-promoting immune actions being the worst.


INTRODUCTION
Tumors may develop from single cells undergoing transformation into a mass of cells that are malignant, through a long process and tiered. In case this happens changes of genetic factors on stem cells undergoing transformation, through a period which could be up to for years, accumulate and eventually settled as a tumor characterized by the growth of cells that can not be controlled lagi.1 During the development process these tumors, a group of cells that undergo transformation, genetically will change the nature of stem cells are normal initially, then grow and become a population of malignant cells that are heterogeneous. Therefore, tumor cells are genetically unstable. This brings the implications of genetic variation of each tumor cells that would complicate the host immune response to recognize antigens expressed by tumor cells tersebut.

It is possible that tumor cells can be recognized by developing new immune system that play a role to get rid of abnormal cells, but certain tumor cells can avoid immune surveillance will continue to grow. Theoretically, the process will involve the development of a tumor is a dynamic equilibrium in the long term, between hosts on the one hand that tried to push the development of tumor and the tumor itself on the other hand are trying to avoid and adapt to the microenvironment where tumor cells are growing so can withstand the attack imun.2 effector cells, 3.4
This situation gave birth to a concept known as immune surveillance and immunoediting. In sum, the successful development of a tumor that consists of a collection of various kinds of cells that have the nature of specific individuals who actually comes from the same cell derivative, but each displays a different genetic changes and have a fairly wide variation in the case against the defense system mechanisms tubuh.3, 5

Cancer and Cancer Immunoediting Immunosurveillance
Immunosurveillance Cancer is an immune response that tried to detect the early development of tumor cells and eliminate the total.5, 6 Clinically this condition is rarely observed, however, laboratory evidence indicates an increase in the incidence of cancers that occur spontaneously or induced a carcinogen, in mice that had immunodeficiency, when compared with normal mice. This provides strong evidence of immunosurveillance.5
On the other hand, although certain tumor cells can be destroyed by the immune system, a type of other tumor cells can grow and develop, where these cells showed reduced immunogenicity, and it has the ability to inhibit the immune response that is protective against cell- tersebut.5 tumor cells, 7 tumor cells are actually composed of a heterogeneous collection of cells, therefore the interaction between the immune system and tumor cells, can show results very varied. This situation gave birth to a concept known as cancer immunoediting.5, 8
In humans, the phenomenon of this immunoediting underlie the increased incidence of cancer triggered by viruses other than, in the post-transplant patients receiving immunosuppressant, when compared with normal individuals. This is supported by the fact that cancer patients are often found in the immune response against neoplastic cells and correlated with the onset of infiltration that is tumoricidal lymphocytes (CD8 +) and are tumor-protective (CD25 + Foxp3 +). For example, in colorectal tumors, the immune response that seemed to be histopathologically, both in quantity and quality is a reliable prognostic indicator. In this case, allegedly adaptive immune responses play an important role to prevent the spread and recurrence, so that the dynamic interaction of the immune system in the face of tumor cells, can affect the mortality of a patient tumor.9

Tumor Antigen
It is a fact, that the immune response against tumors usually will not be optimal to eliminate malignant cells, especially to prevent the occurrence of a metastasis. On the other hand, the patient is still capable of providing an adequate immune response against microbes through a danger signal, but rather the immune response to tumor antigens not regard it as something dangerous (regarded as a self antigen). The differences are very basic introduction to these antigens, increase the chance or the ability of tumor cells in response imun10 avoiding, 11
The immune system can provide a response to neoplastic cells through 2 types of antigens which diekspresikannya, namely;
- tumor-specific antigens, a typical molecule in the tumor cells, the production of a mutation of the genes of normal cells and are usually induced by a carcinogen. These mutant proteins can be recognized as an immune system protein asing12, 13
- tumor-associated antigens, in the form of molecules expressed by neoplastic cells that can be distinguished from normal cells. Such tumor antigens are usually induced by a virus. An example is a protein molecule produced by the genes E6 and E7 from human papillomavirus (HPV), as the causative agent of cervical carcinoma and EBNA-1 (Epstein-Barr virus nuclear antigen) is expressed by cells of Burkitt's lymphoma and carcinoma nasopharyng13
Dendritic cells as antigen presenting cells (APC), can break proteasom cells of normal and neoplastic cells into peptides that will be presented at the cell-cytotoxic CD8 + T cells through the molecules of the major-histocompatibility complex (MHC) class I. In addition, peptides derived from genes that are mutated or derived from neoplastic cells, can be presented by APC in the cell-CD4 + T cells through MHC molecules class II14, 15

Kinds of immune response against the neoplasm
Immune cells against neoplastic cells of the immune response can be either natural (innate) and acquired (adaptive). Natural immune system mediated by immune cells (macrophages, granulocytes, natural killer cells / NK cells, T cell gamma / delta) and soluble factors (complement, C-reactive protein / CRP, mannose binding protein / MBP, serum protein amyloid). While the adaptive immune response mediated by T cells that recognize peptides derived from neoplastic cells, when the peptides were presented by the APC through MHCnya.3 molecules by complex recognition of tumor peptide receptor (TCR), both contained on CD4 + T cells and CD8 + T cells, will initiate the process that will sinyaling can activate T cells This mechanism can be viewed as a primary immune response which in turn can develop into effector cells that are anti tumor.3, 16
Immune response against malignant cells may be local, regional or systemic. Localized immune response that can be known from the til (tumor infiltrating Lymphocytes) that can hold accumulated in several solid tumor tissue and are thought to inhibit tumor progression, but on the other hand may also experience defek.3, 17
Systemic immune response against the tumor as measured in the peripheral circulation or through an examination of DTH (delayed type hypersensitivity), it seems difficult to be demonstrated, because the specific immune response against systemic tumor is still difficult to comprehend. Recent studies indicate, that the defects that occur in the til, may also occur systemically, as well as defects of lymphocytes in lymph nodes contained cancer. This may indicate that cancer can cause a strong suppressive effect on specific immune system both locally or sistemik3.

Cells - immune cells as Anti-Tumor Response

Lymphocytes
Among the immune cells that had infiltrated around the tumor, T cells (CD3 + TCR +) is the largest component, although from some research suggests that this type of cytotoxic cells (CTL) is relatively lower when compared to peripheral blood cell lymphocytes as a whole. Although the lymphocyte CD4 + or CD8 + were isolated from tissues indicated in the activated state, but functionally does not show a normal function. Til obtained from metastatic lesions or advanced-stage cancer generally indicate a functional defect is more evident, when compared with that derived from the lesion that is still early. This can lead to suspicion that the tumor tissue can suppress the immune system, so as to reflect the functional status of a TIL.3, 5.8
 chain expression of the molecule which is a component that connects sinyaling TCR complex with nuclear factor kappa B / NF   (a transcription factor that served to regulate the expression of inflammatory genes and mediators of the immune system), has been widely studied has links with the function T cells Lymphocyte infiltration in tumor tissue of a patient where  molecule expression is low or not visible at all, have a life expectancy five years lower than the expression of its molecular  normal.18 In addition, T cells that express CD95 + (also called Fas is a member of the TNF family receptors and function in the process of cell apoptosis) is a dominant T cell population found in the circulation of cancer patients. These T cells (CD3 + CD95 +) are more likely to hold a bond with Annexin V (Anx), which then increase the activity of caspase-3 and decreased expression of molecules . This process will lead to apoptosis of T cells, which eventually involved contributed to the weakening of effector cells of the immune system against tumor.14

NK cells
NK cells (CD3-CD56 + CD16 +) that plays an important role in natural immune system, complemented by perforin and granule-granule-containing granzym that can facilitate the occurrence of lysis of tumor cells. However, almost all tumor cells are resistant to the effects of perforin and therefore, NK cells are rarely found in Til. This can be explained, that NK cells are found in more premalignan lesions or early-stage lesions and rarely tumor tissue obtained from an advanced stage, where all these circumstances in accordance with the concept of the role of NK cells in immunosurveillance, compared with its role in terms of killing the cells kanker.20
In addition, NK cells have a receptor called NKG2D an important role in immunological recognition of cells undergoing stress. Ligands of these receptors (Rae-1), often expressed by cells infected with viruses or cells undergoing DNA damage, and always expressed by tumor cells. Rae-1, is a target of immunoediting process which is also played by   T cells that function as editors.21


Dendritic cells
Dendritic cells play a role in terms of memfagosit, process and present tumor associated antigens (TAA) to CD4 T cells, thus timbuk effector cells against tumor-specific. These dendritic cell infiltration in tissues around the tumor, has a long association with better survival in patients with carcinoma of the bladder, lung, laryng, oral, and gastric carcinoma nasopharyng.22
On the other hand, tumor associated dendritic cells (TADC) directly exposed to the tumor or factors derived from tumors (gangliosid) that can interfere with the process maturasinya or even more susceptible to apoptosis. Suppressive effect of this gangliosid mediated by VEGF (vascular endothelial growth factor) which has been known as a factor inhibiting dendropoesis.23

Macrophages (CD14 +)
Seacara normal, macrophage function as APC that important role in controlling the infection process. In tumor tissue, these macrophages (tumor associated macrophages / TAM) suffered the reprogramming process by tumor cells through the release of specific cytokines, prostaglandins, or reactive oxygen metabolites (ROM), so that it can inhibit lymphocyte function. However, another study claimed, in breast cancer, increased infiltration of macrophages is a predictor of decreased likelihood of a recurrence of tumor tersebut.3

B cells (CD19 + CD20 +)
B cells are rarely found in tumor tissues, with the exception of breast cancer and melanoma. B cell function is differentiate into plasma cells that can produce antibodies. Specific antibodies against TAA can be detected in circulation in patients with cancer, in which the antibody is secreted by the regional lymph nodes around the tumor, lymph nodes or other lymphoid tissues. Although this is often the presence of B cells in the tumor tissue did not significantly affect the clinical condition, but this can be considered as an important aspect of defense mechanisms tubuh.3

Role of Inflammation
It has been much discussed role of the immune system as an element in the body's defense against cancer. However, in some animal experiments indicate that the mechanisms of inflammation, may trigger the development and growth of a tumor. In this case the question could arise, how is the actual role of the immune system, whether as a body protection against tumors can be induced or even vice versa? There is a dichotomy that places cancer immunosurveillance and cancer immunoediting one hand, while on the other hand put the chronic inflammatory process as the originator of the malignancy. This leads to an opinion, that these two opposing processes that stand in isolation. But the two mechanisms could be something that overlap or an algorithm. In other words, the claim that the immune system can prevent or induce cancer, must be accompanied by evidence of specific immune system components which play a role in each of these processes diatas.24, 25.26 For example, T cells CD4 + a protective immune cells in mice that had cervical carcinoma through induction of HPV, whereas in skin malignancy, the cells were CD4 + T and B cells can actually menginduksinya.27, 28.29 Another opinion says, the T cells can induce   occurrence of cancer induced by high doses of carcinogens, whereas blocking   T cells on carcinogen dose rendah.30
From these animal experiments, may process immunoediting and tumor promoting inflammation can occur simultaneously, or occur in a sequence in which inflammation precedes immunoediting which can induce the occurrence of transition, between preneoplasma and neoplasms or inflammation can occur after a process of immunosurveillance, probably by inducing the transition from phase equilibrium to escape the second phase represents the phases of the immunoediting.31, 32

Regulatory Mechanisms in Cancer
In the blood circulation of cancer patients, found the cells supressor T lymphocytes that can inhibit the function / activity of other immune cells, especially against tumors. T cells of this type, identified as T cells and CD4 + CD25 + cells called regulatory T cells. In animal experiments, the depletion of T cells of this regulator will be able to enhance immune responses against autologous tumor. The mechanism of suppression of antitumor responses by regulatory T cells is mediated by the cytokines TGF- and IL-10.2, 3

Summary
The tumor is a collection of cells that underwent a transformation and then grow and develop without being able to be controlled anymore. The genetic changes occur from the nature of cells that then express specific antigens that can be recognized by the immune system. Immunosurveillance mechanisms ought to immediately eliminate these cells, but in reality, seed cells continue to develop this neoplasm. Because it is very heterogeneous, the interactions between immune system and tumor cells, producing a wide range of possibilities. In this case immunoediting mechanism has an important role.
Various kinds of immune cells, either from natural elements and adaptive immune responses can take the specific role of each stage of the mechanism of host immune response against tissue neoplasms.
However, the inflammatory response in some circumstances it can trigger malignant transformation. Both these opposing circumstances, may occur as a separate, overlapping or an algorithm, the immune response against neoplastic cells. This requires a more in-depth research.
A subset of T cells, referred to as imunoregulator may play inhibits an immune response against tumors in the future need to be revealed clarity.