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A tumour also called as neoplasm, is abnormal growth of body tissues. Its of 2 types, cancerous malignant and non-cancerous. Annual report by American cancer society reported 5,71,950 deaths from 15,96,670 cancer patients, in 2011 , showing a need of effective cancer treatment.
Before understanding the immunity against tumour, one must know the changes that happen in the normal cells during tumour formation. Tumour formation mainly occurs due to changes in the gene expression. Alterations in membrane receptors, regulators of cell cycle, apoptosis or molecule involved in the signal transduction are also observed which causes alteration in antigens present on the normal cells.
Body has tumour rejection mechanism called as tumour immunity. The main immune system working against tumours is cell mediated immunity. Various T cells and B cells both are involved in the tumour immunity, but T cells play a main role. T helper (Th), T regulatory (Treg), T effector (TE), T cytotoxic (Tc), natural killer T cells (NKT) are the cells involved in the tumour immunity. There are 2 main types of tumour antigens, tumour specific transplantation antigen (TSTA), which are unique to tumour cells and expressed on the normal cells and tumour associated transplantation antigens (TATA) that are expressed by both tumour and normal cells. TATAs are expressed during development of cells and lost as age increases and re-expressed in tumours.
The problem comes when immunity against tumours is supressed. It has various reasons like, tumours may fail to express molecules for co-stimulatory signals which is required for activation of t cells, poor MHC antigen expression, early development of tumours, small amount of antigen against tumour, rapid tumour proliferation might be other reasons for inappropriate tumour immunity. Immune tolerance is the process in which the immune system of body does not act against the self or non self antigens. It is of 2 types natural / self-tolerance through which body does not attack self antigens and induced system . Reactivity of immune cells depends upon the environment in which they develop, hence this study will improve our understanding about their functions, pattern of migration and survival characteristics  which will help in treatment against tumour. Tumour immunity is a part of an autoimmunity .
Regulatory T cells in tumour immunity
Regulatory T cells are important for maintaining unresponsiveness against self antigens and for preventing the deleterious effects due to excess of immune response . T regulatory cells are produced in the thymus in the form of functionally mature T cells and later on form functionally distinct T cells subpopulation in the periphery. Foxp3 CD25+CD4+ are 3 important Treg cells involved in tumour immunity which play major role in immunological self-tolerance . It also helps in immune homeostasis in which Treg supress physiological and pathological immune response against self and non self . Removal of T cell subpopulation increased the tumour immunity. Clonal anergy and control of self-reactive T cells help in immunological self-tolerance.
CD25+ CD4+ Treg cells
CD25 expressing T cells occupy 5-10% of the peripheral CD4+ T cells of blood. Large number of CD25+CD4+ Tregs are found in draining lymph nodes in head ,lung, liver, neck, gastrointestinal tract, pancreas, ovary & breast of cancer bearing individuals . CD25+4+ cells when removed, the amount of secretion of IL-2 was increased which in turn increase in the number of CD8 T cytotoxic cells. In the individuals who are unresponsive to the antigens, removal of Cd25+4+ T cells showed responsiveness to the autologous tumour in vivo and also in vitro. Both tumour specific and nonspecific antigen production was seen. CD25+ removal increased the lifespan of tumour containing individual, this can be also performed by administration of anti CD25 mAb . Treg not only suppresses the cytokine production but also maintains development of CD4 cells in later stages of immune responses . Depletion of CD25+CD4+ T reg by an immunotoxin conjugated with IL-2 (DAB389IL-2) resulted in increased inhibitory response against tumour . Although CD4 T cells act as suppressors and its removal helps in better tumour antigen response , some scientists found out importance of CD4 cells in tumour immunity[10,11]. It has been found that CD4 help, its magnitude and CTL activity are inter-related. There is also correlation between CD8+ and CTL cells hence CD8 and CD4 interconnection is seen. Decrease in level of CD8 and CD4 cells below 107 cells reduces the anti-tumour ability. Transfer of CD4 and CD8 cells after 7th or 14th day of tumour inoculation did not show any immunity against tumour, hence proving the need of these cells to be present at earlier stages of tumour growth.CD4+ cells are important for production of IL-2 and also helps in differentiation of cytotoxic effectors which contributes to the anti-tumour responses. Reason for need of 1:1 ratio of CD8+:CD4+ cells still unclear. Trafficking of CD8 T cells to tumours is directed by CD4 T cells, hence post licensing by CD4 helps in CD8+ infiltration of tumours.
Foxp3+ T cells
Foxp3 is a transcription factor, deficiency or dis functioning of which may cause autoimmune disease , because it controls regulation and development of Treg . At the time of antigenic stimulation they are induced from naÃ¯ve T cells in the presence of TGF-Î² . There is possibility that immature dendritic cells get activated by tumours to secrete TGF-Î² which contribute to conversion of naÃ¯ve cells in Foxp3+CD25+CD4+ Tregs. Foxp3 performs many important tasks, they controls gene coding for surface molecules, such as CD25, GITR family regulated gene, CTLA-4 [15,16], it also secretes IL-10, TGF-Î², IL-35 which are immunosuppressive. Hence Foxp3 have ability to suppress wide variety of self and non self-antigens and they are IL-2 dependent for their survival[7,18]. It can suppress response of CD4+ helper T cells, CD8+ cells, natural killer cells and natural killer T cells. Enhanced natural and induced tumour immunity was observed on removal of Foxp3 Treg cells . Foxp3 Treg and Teff cells have similar pattern of surface molecules, hence it is difficult to target both the cells separately .
CD8+ Teff cells in tumour immunity
CD8+ T cells are effector T cells which are involved in cytotoxic T lymphocyte production and hence act against the tumour formation. Secretion of INF-Î³ play important role in tumour rejection . Analysis of tumour bearing patients showed that suppression of CD8+ T cells increases with tumour progression because as tumour progresses the accumulation of tumour specific CD8 and CD4 cells occur at the tumour site and hence suppression of CD8 cells happens. This shows that CD8 cells fail to undergo normal functional maturation in presence of Treg cells, which abolish their cytotoxic function . In one of the studies where TGF-Î² receptor was replaced by dominant negative TGF-Î² receptor, resistant to suppression is observer which shows that TGF-Î² receptors on cytotoxic T cells are involved in suppression . Elimination of CD8+ t cells completely abolished the anti-tumour ability of body, where CD4+ T cell elimination did not result in complete immune loss against tumour, showing importance of CD8+ T cells in tumour regression . Cyclophosphamide is a drug which removes CD25+CD4+ Treg cells but not T effector cells. Administration of this drug increased CD8+ t cell response and hence better anti-tumour activity .
T helper cells in tumour immunity
CD4= t cells differentiate into various subsets of T helper cells like Th1, Th2, Th17 and T follicular helper cells. Out of these cells Th17 is important as it produces IL-17A, IL-17F, IL-22, IL-23 cytokines. Inhibition of IL-17A leads to inappropriate defence against bacteria and also resistance to autoimmune diseases. IL-23which is highly expressed by Th17 can induce tumour specific immunity against melanoma and glioma. Tumour specific TH17 cells do not act directly on melanoma cells, it triggers production of CD8+ cells. Enhanced tumour growth is observed in absence of IL17, possibly due to inappropriate regulation of chemokine mediated leukocyte migration into tissues. One of the studies on lung melanoma found out the mechanism of action of Th17 cells. It says that Th17 cells go to the tumour site and secrete IL-17 which produces CCL2 & CCL20 mobilizing DCs. DCs take up tumour antigens and migrate to lymph nodes which activates CD8+ T cells, that migrates back to tumour site and kills the tumour. Comparison of Th17 cells with Th1 cells showed that Th17has greater ability to activate granulocytes, macrophages and DCs than Th1 cells. IL-17 deficiency increases susceptibility to cancer.
TEM & TCM cells
T memory cells are of two types, on the basis of phenotypic markers, functional attributes & migratory properties, one is effector memory CD8+ T cells (TEM) and other is central memory CD8+ T cells (TCM). To check the potential of anti-tumour activity of different types of CD8 cells, IL-15 and IL-2 were used to produce TCM & TEM respectively. It is found that homing of T cells to secondary lymphoid organs is important for anti-tumour activity. Hence secondary lymphoid tissue targeting is more important than tumour sites hence TCM are superior to TEM cells for immunotherapies . TEM can also generate secondary response but efficiency is less than TCM .
IL-2 is required for expansion of CD8+ T cells and for production of lymphokine activated killer cells. Direct addition of IL-2 into CD8- cell culture can augment CD8 T cell mediated tumour immunity . TLR signals partially blocks the suppressive action of Treg cells by mechanism which is IL-2 dependent . IL-2 also maintains Foxp3 Treg cells .
CTLA-4 is negative immunomodulator. It is expressed on activated t cells and helps in delivery of suppressive signals produced by CD25CD4 cells. Blockade of CTLA-4 inhibits suppressive activity of Treg cells. Treatment with CTLA-4 mAb resulted in long term clinical response in melanoma patients .
The recent studies are going towards the combination of various treatments for tumours. The combination of irradiation and T cell immune therapy is proved to be very successful in tumour treatment. Irradiation generally decreases T cells of the body, it also increases expression of the effector cytokines IFN-[gamma] and TNF-[alpha] by donor and host CD4+ and CD8+ T cells. Hence irradiation followed by CD8+ T cells therapy increases anti-tumour response .
Th17 cells have stem cells like structure and hence it produces long term immunity .
The importance of CD8+ T cells in tumour immunity makes them attractive target for tumour vaccines. To produce vaccines quality magnitude and duration of CD8 T cells has to be controlled. mTOR can regulate CD8 cell functions. Administration of various amounts of drug Rapamycin can regulate viral vaccine induced CD8+ T cells responses of tumour immunity .
CCR5 expression by both CD4+ & CD8+ T cells is important for production of anti-tumour responses. This study can help to treat CCR5 deficient tumour patients .
Tumour cells can hide their surface antigens from effector cells by process called antigenic modulation. Tumour growth favours generation of suppressor T cells. CD8+ T cells are important for anti-tumour activity. T regulatory cells can interfere at early stages of CD8 immune response. CD4+CD25+ regulatory T cells are negative regulators of T cell anti-tumour response in vitro and in vivo. Depletion of Foxp3 Treg cells or attenuation of its suppressive functions can enhance anti-tumour activity. IL-17 produced by Th17 cells play important role in prevention of tumour. TLR ligands, anti CTLA-4 mAb, Denileukin difitor, Cyclophosphamide, Rapamycin are reagents that can be used to enhance tumour immunity. Combination therapy which targets different T cells and antigen presenting cells is promising anti-tumour immunotherapy. More accurate targeting of antigens expressed by tumours is required for better immunotherapy.