Date of Award
Dr. Tim Knight
Dr. Lance Bridges
Dr. Brian McKinney
Cutaneous T-Cell Lymphoma (CTCL) is a deadly form on non-Hodgkin lymphoma that primarily affects the skin. Non-Hodgkin lymphoma means that the lymphoma does not have the presence of Reed-Sternberg lymphocytes. A lymphoma, also known as lymphatic cancer, affects the lymphoid tissues, which plays a major role in the immune system. Lymphoid organs include the lymph nodes, thymus, spleen, and bone marrow. Lymphatic fluid, also known as lymph, travels through the bloodstream to transport lymphocytes, a type of white blood cell, to and from lymphatic organs. Due to a high concentration of lymphocytes in the skin, lymphoma primarily affects cutaneous areas.
There are many classifications and presentations of CTCL. The most common form is mycosis fungoides. Mycosis fungoides is presented as pink itchy rash made up of rapidly dividing T-cells that have made their way from to blood into the skin. These cells target the skin due to their expression of the skin-homing receptor cutaneous lymphoid antigen. These are primarily CD4+ memory T cells. CD4+ memory T cells are a form of helper T cell, which are tasked with marking foreign cells for later destruction by CD8+ cells, also known as cytotoxic, or “killer” T cells. Currently there is very little understanding of the disease etiology or origin.
There is currently one FDA approved retinoid for CTCL treatment, Bexarotene (Targretin®). Bexarotene is among vitamin A derivatives that affect many processes. These include but are not limited to cellular differentiation, apoptosis, and proliferation. Retinoids operate by binding to retinoic acid receptors (RAR) and retinoid X receptors (RXR). Among these RAR and RXR receptors are three subtypes of each (-α, -β, and -γ). Ligand activation of these subtypes typically result in the dissociation of corepressors that control proliferation and differentiation. In simpler terms, binding of ligands to these receptor proteins will induce cellular reproduction and specialization. Unfortunately, Bexarotene has been found to cause serious side effects such as hyperlipidemia, hypercholesterolemia, and hypothyroidism. These side effects can be found in roughly one-in-five users, and it has a particularly high prevalence in African American males. Hyperlipidemia results in a higher concentration on lipids in the blood, which can result in the restriction of blood flow. Hypercholesterolemia is an excess in blood cholesterol, excluding triglycerides, which can lead to heart disease. Hypothyroidism is the underactivity of the thyroid gland, which produces thyroid hormone. Imbalance in thyroid hormone can result in abnormal heart rate, body temperature, and metabolism.
Understanding the molecular function of retinoids and how they affect CTCL will be beneficial in future attempts to synthesize drugs with a higher specificity, hopefully eliminated the metabolic side effects that affect its patients.
Retinoids have long been used as an anti-infective agent, and it is known from previous research that non-malignant T-cells use retinoid binding to induce the differentiation into mucosa-associated lymphoid tissues (MALT). It is also known that exposure to Bexarotene induced the expression of integrin protein β7 and the chemokine receptor CCR9. These proteins facilitate lymphocyte homing to the digestive tract. It is possible that exposure to Bexarotene can “trick” a cancerous cell into “thinking” that is belongs in the digestive tract. A gut lymphocyte found in the skin would likely not be able to survive its environment, making it a plausible cause for apoptosis and CTCL treatment. The goal of this project is to determine if retinoids cause a level of cellular differentiation by determine the expression of two known T cell transcription factors (FOXP3 and ROR-γ) within CTCL lines.
In this experiment, experiments were run to collect data to determine: baseline levels of FOXP3 in human CTCL cells vs. healthy cells, rates of cell death when treated with different isoforms of RXRs and RARs at varying concentrations, the degree to which cells can recover after retinoids have been removed from the media, synergism when treated with pairs of different isoforms, and baseline levels of FOXP compared to ROR-γ and T-Bet in human CTCL lines.
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Kendrick, Baker, "Retinoids and their Clinical Benefits to Treating Cutaneous T-Cell Lymphoma" (2023). Honors Theses. 889.