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Regulatory T cells and their targeting for cancer therapy

Definition and markers of regulatory T cells

The major function of the immune system is to protect the organism from a variety of pathogens, such as bacteria, fungi and viruses, and thereby to preserve the integrity of the body. This is possible due to the ability of the immune system to recognize „self” and respond to „non-self” in a process of  immune response.  Importantly, in order to maintain the immunological self-tolerance and simultaneously to eliminate the danger triggered by harmful pathogens, the activity of the immune system needs to be tightly regulated. The essential role in this regulation is played by various subpopulations of CD4+ T lymphocytes, the majority of which are helper T cells (Th) that promote the immune response. In turn, the specific CD4+ T cells, so called regulatory T cells (Tregs) quench the immune response and are considered as one of the main mechanisms that protect the host from autoimmunity.

Cancer genetics influences efficacy of current immunotherapies

Cancer immunotherapy has recently emerged as a forefront strategy to fight cancer with long-lasting clinical benefits, especially for patients who have metastatic disease. Most of currently available immunotherapies improves the natural anti-cancer responses of the immune system, mediated by T lymphocytes.

Immune checkpoint blockade in cancer treatment

What are immune checkpoint receptors?

Adaptive immune system consists of highly specialized groups of immune cells that are able to recognize and respond to specific antigens in order to defend the organism from foreign, but also inner threats, such as cancer cells. Detection of foreign cells occurs upon binding of T-cell receptor (TCR) on T-cells to peptides displayed by major histocompatibility complex (MHC) proteins on a cell presenting the given foreign antigen. However, in order to tightly control the adaptive immune responses, T cells receive a series of co-stimulatory or co-inhibitory signals via receptors and their ligands collectively referred to as “immune checkpoints”. The immune checkpoints are key regulatory molecules that in physiological conditions have a task to maintain immune homeostasis. To this end, immune responses must be fine-tuned to allow effective removal of invasive pathogens, while maintaining tolerance to auto-antigens. Too strong immune response to pathogens or defective self-antigens could cause tissue damage and autoimmune diseases.

Immunotherapy with monoclonal antibodies

Therapy with monoclonal antibodies (mAbs) (https://www.youtube.com/watch?v=Na-Zc-xWCLE) is currently the most popular method of immunotherapy (https://www.youtube.com/watch?v=K09xzIQ8zsg) used in the treatment of cancer and other diseases. Monoclonal antibodies (https://www.youtube.com/watch?v=0A99pk6kpS4) are antibodies derived from the same clone of B cells that recognize with equal specificity the same antigen fragment, known as epitope. Thanks to the hybrydoma technology (https://www.youtube.com/watch?v=O-SrPqJuEVg) developed in 1975 by Nobel Prize winners-Milstein and Köhler (http://www.whatisbiotechnology.org/index.php/exhibitions/milstein), and then improved with advances of genetic engineering, it is now possible to produce on a large scale monoclonal antibodies that can recognize any given antigen. These monoclonal antibodies can detect proteins that are used as therapeutic targets in the treatment of various human diseases.

STING protein

Introduction

One of the major roles of the immune system is to discriminate self from non-self and to protect organism from pathogens and other foreign invaders. To do this, it employs an elaborate system of sensors dedicated to detect foreign molecules, so called ‘danger signals’.

IDO - Indoleamine 2,3-dioxygenase

Introduction

Inflammation is a well-organized process that plays a crucial role in protection against pathogens. However, the breach of regulation of an immune response can be dangerous and may result in a wide range of chronic immune reactions including autoimmune diseases. Thus, the control of inflammation is pivotal to limit cellular and organ damage. Many different mechanisms are involved in immune cells inhibition and silencing the immune response. An enzyme, named indoleamine 2,3-dioxygenase 1 (IDO-1, IDO), is an example of an immunoregulatory mechanism that generates an immune tolerance to antigens in the tissue microenvironment. The function of IDO has been first demonstrated by Munn, Mellor and their colleagues, who have shown the pivotal role of IDO in the protection of mammalian fetus from maternal T cells. They demonstrated that the expression of IDO by murine placenta cells is crucial to prevent fetus destruction by maternal immune cells during the pregnancy. Since that time researchers focused on the investigation of the immunoregulatory functions of IDO, also in mediating tumor immune evasion.

Role of L-arginine in tumor immune surveillance

 

Immune surveillance is a host protection process, in which the immune system detects and destroys pre-cancerous and cancerous cells before they can progress and threaten the body.

The role of tumour microenvironment in cancer immunotherapy

A malignant tumour is a complicated collection of a vast array of cells. Cancer cells are accompanied not only by tumour stroma blood and lymphatic vessels but also by a significant amount of tumour-infiltrating immune cells. The role of immune cells found in the tumour microenvironment is more than complex.

NK Cells applications in immuno-oncology

Natural killer (NK) cells are immune cells that constitute 5%-15% of lymphocytes. They were discovered and described in 1970s and since then have been extensively studied due to their unique capabilities of killing target cells. NK cells are critically involved in response against tumor cells or virally infected cells. Once the target cells are recognized, they are destroyed by NK cells within minutes in a mechanism known as cytotoxicity. NK cell cytotoxicity is tightly regulated through the complex balance between inhibitory and activating signals originating from different NK cell receptors.

Chimeric antigen receptors (CARs)

Adoptive cell transfer (ACT) is a form of cancer immunotherapy which involves engineering of primary immune cytotoxic cells (T or NK cells) to recognize and attack tumor cells. Recently, a modification with chimeric antigen receptors (CARs), generated some remarkable responses in patients with advanced cancer.

 

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