Treg and Tmem in Immunotherapy Platform: A Twilight of Life-long Immunity against Cancer and Infection for Future Decade

94 Behind the Immunotherapy platform Nobel Laureates of medicine in 2011 showed that the immune system fight against cancerous tumor and Ralph Steinman one of the Nobel Laureates of medicine in 2011 discovered dendritic cells and their unique capacity to activate and regulate adaptive immunity and the later stage of the immune system to clear microorganism from the body. Dendritic cells are the potential immune cells to represent the antigen to T-Cells against foreign bodies in the biological system. There are various types of T-Cells like Th1, Th2, Th3, Th17, ThFM, Treg, Cytotoxic CD8 T-Cell, and memory T-cells (Tmem). On the basis of the functions of these T-Cells, Immunotherapy and thereby immune engineering were being processed to innovate future vaccination.

2 95 There are several types of immunotherapy, including: a) Monoclonal antibodies, b) Non-specific immunotherapies, c) Cancer vaccines and d) Oncolytic virus therapy,

Monoclonal antibodies
When the body's immune system detects something harmful, it produces antibodies. Antibodies are proteins that fight infection.
Monoclonal antibodies are a specific type of therapy made in a laboratory. They are designed to attach to specific proteins in a cancer cell. These therapies are highly specific, so they do not affect cells that do not have that protein.
Monoclonal antibodies are used as cancer treatments in various ways: To allow the immune system itself to destroy the cancer cell. The immune system doesn't always recognize cancer cells as being harmful. This is one of the ways that cancer can grow and spread. Researchers have identified the PD-1 pathway as being critical to the immune system's ability to control cancer growth. Blocking this pathway with PD-1 and PD-L1 antibodies can stop or slow cancer growth. These immunotherapy drugs may be referred to as checkpoint inhibitors because they interrupt an important part of the immune system process. Examples of checkpoint inhibitors include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda). Additional drugs are being studied.

Non-specific immunotherapies
Like monoclonal antibodies, non-specific immunotherapies also help the immune system destroy cancer cells. Most non-specific immunotherapies are given after or at the same time as another cancer treatment, such as chemotherapy or radiation therapy. However, some non-specific immunotherapies are given as the main cancer treatment.
Two common non-specific immunotherapies are: Interferons. Interferons  Interleukins. Interleukins help the immune system produce cells that destroy cancer. An interleukin made in a laboratory, called interleukin-2, IL-2, or aldesleukin (Proleukin), is used to treat kidney cancer and skin cancer, including melanoma. Common side effects of IL-2 treatment include weight gain and low blood pressure, which can be treated with other medications. Some people may also experience flu-like symptoms.

Cancer vaccines
A vaccine is another method used to help the body fight disease. A vaccine exposes the immune system to an antigen. This triggers the immune system to recognize and destroy that protein or related materials. There are two types of cancer vaccines: prevention vaccines and treatment vaccines.

Prevention vaccine.
A prevention vaccine is given to a per-son with no symptoms of cancer. It is used to keep a person from developing a specific type of cancer or other cancer-related disease. For example, Gardasil and Cervarix are vaccines that prevent a person from being infected with the human papillomavirus (HPV). HPV is a virus known to cause cervical cancer and some other types of cancer. In addition, the U.S. Centers for Disease Control and Prevention recommends that all children should receive a vaccine that prevents infection with the hepatitis B virus. A hepatitis B infection may cause liver cancer.

Treatment vaccine.
A treatment vaccine helps the body's immune system fight cancer by training it to recognize and destroy cancer cells. It may prevent cancer from coming back, eliminate any remaining cancer cells after other types of treatment, or stop cancer cell growth. A treatment vaccine is designed to be specific, which means it should target the cancerous cells without affecting healthy cells. At this time, sipuleucel-T (Provenge) is the only treatment vaccine approved in the United States. It is designed for treating metastatic prostate cancer. Additional cancer treatment vaccines are still in development and only available through clinical trials. Recent findings provided a preclinical rationale to apply CD27 agonist antibodies, either alone or combined with PD-1 blockade, to improve the therapeutic efficacy of cancer vaccines and immunotherapy generally .

Oncolytic virus therapy
Oncolytic virus therapy is a new type of immunotherapy that uses genetically modified viruses to kill cancer cells. First, the doctor injects a virus into the tumor. The virus enters the cancer cells and makes copies of itself. As a result, the cells burst and die. As the cells die, they release cancer antigens. This triggers the patient's immune system to launch an attack on all cancer cells in the body that have those same antigens. The virus does not enter healthy cells.
In October 2015, the U.S. Food and Drug Administration approved the first oncolytic virus therapy to treat melanoma. The virus used in the treatment is called talimogenelaherparepvec (Imlygic), or T-VEC. The virus is a genetically modified version of the herpes simplex virus that causes cold sores. The doctor can inject T-VEC directly into melanoma lesions that a surgeon cannot remove. Patients receive a series of injections until there are no lesions left.
A potential issue limiting the immune response to vaccination is the presence of regulatory T cells (Tregs) that suppress T cell activation , .

T reg , Regulatory T-Cells
T reg is functionally known as CD4 + CD25 + FOXP3 + . They play a great role for keeping peripheral tolerance, preventing auto immune diseases and also controlling auto immune disorders. A selective increase of the chemokines CXCL9 and CXCL10 in T regcell-depleted tumors, which was accompanied by accumulation of CXCR3+T cells, increased IFN-γ mRNA expression. T reg -cell depletion increases the accumulation of conventional T cell 5 .

T reg in Tumor Hypoxia environment
Tumor hypoxia promotes tolerance and angiogenesis via CCL28 and T reg cell

Figure 3. T reg cells in Hypoxia and CCL28 MEC, mucosa associated epithelial chemokine (Facciabene A et al. 2011) 6
T reg and Tumor-Specific CD8+ T Cells in tumor microenvironment Suppression of Tumor-Specific CD8+ T Cells by Regulatory T Cells T reg and T reg cells secrete interleukin-10 as well as transforming growth factor-beta1, mediates immune suppression in the tumor microenvironment . The following figures (Figure 4 and Figure 5) illustrated that suppression of T reg increased the population of CD8+ T cells and interferon gamma secretion. These events outcome of a promising antitumor activity. Epitope antigen successively can control such kind of suppression of T reg , which can potentiate functionally future Protein/DNA vaccine. T reg depletion improves the efficacy of vaccines against pathogens in mice . Therefore, vaccine strategies that target both the innate and adaptive immune systems for the generation/upregulation of potent anti-pathogenic immune responses and simultaneously overcome T reg -mediated immune inhibition are more likely to succeed. Mice vaccinated with Tat-E7/pGM-CSF generated a significantly higher amount of CD3+CD8+CD45RO+ T memory cells, as compared to those mice vaccinated with the control agents (P < 0.01). Low levels of SIV infection in sooty mangabey centralmemory CD4+ T-cells is associated with a limited CCR5 expression that caused the host uninfected  T memory/effector cells (Tmem/off) isolated from psoriasis patients are chronically activated and poorly suppressed by regulatory T cells (T reg ). The proinflammatory cytokine IL-6, which signals through Stat3, allows escape ofTmem/ effcellsfromT reg -mediated suppression in a marine system. One research group showed that IL-6 protein was markedly elevated and most highly expressed by CD31 (+) endothelialcellsand CD11c (+) dermal dendritic cells (DCs) in lesional psoriatic skin. They hypothesized that exposure to high IL-6 in lesional tissue may lead to the dampened T reg function observed in psoriasis patients .
Activation of Th17 cells in experimental autoimmune encephalitis is associated with the escape of Teff from T reg control . Given that IL-6 signaling leads to a loss of T reg function (Fig. 5�), IL-6-producing cells in the lesion likely contribute to the reactivity of tissue Teff by dampening normal T reg control mechanisms. As a critical factor in the homeostatic balance between Th17 cells and T reg , the high levels of IL-6 generated by DCs and endothelial cells in lesional skin likely tips the balance in favor of pathogenic Th1 and Th17 cells over T reg , further allowing for unrestrained T cell activation. Thus, targeting IL-6 and its downstream signaling pathways within the lesional psoriatic skin holds promise in the restoration of functional T reg control over Tmem/off activation.
One research group presented the evidence for intranasal delivery of the model antigen ovalbumin (OVA) along with alpha-galactosylceramide adjuvant as a protein vaccine to induce significantly higher levels of antigen-specific effector and memory CD8� T cells in the FRT (Female Reproductive Tract), relative to other systemic and mucosal tissues. Antibody blocking of the CXCR3 receptor significantly reduced antigen-specific CD8(+) T cells subsequent to intranasal delivery of the protein vaccine, suggesting an important role for the CXCR3 chemokine-receptor signaling for T cell trafficking. Further, intranasal vaccination with an adenoviral vector expressing OVA or HIV-1 envelope was as effective as intramuscular vaccination for generating OVA-or ENV-specific immunity in the FRT. These results supported the application of the needle-free intranasal route as a practical approach to delivering protein as well as DNA/virus vector-based vaccines for efficient induction of effector and memory T cell immunity in the FRT.

Conclusion
Central memory CD4+ RO+ and CD8+T RO+cells were very effective at suppressing viral replication. Evaluating and developing the Central memory CD4+ RO+ and CD8+T RO+cells in immunization by both DNA and protein vaccine, life-long antigen specific immunity might be possible against cancer and many other fatal diseases ahead.