The clinically relevant role tregs play in establishing an immunosuppressive tumor microenvironment in melanoma
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The study of regulatory T cells (Tregs) is a relatively new field. Within the past few decades, research on Tregs has greatly deepened scientists’ understanding of the link between the immune system and cancer. The study of melanoma is one such cancer that has benefited greatly from this area of study. Tregs are a subset of CD4+ T cells (TCs) that are either generated in the thymus or in the periphery. The main role of Tregs in normal immune physiology is to suppress immune cells. This is an essential component in the prevention of autoimmunity. In melanoma, however, Tregs prevent components of the immune system from mounting a robust response to cancerous lesions and tumors. Tregs have been observed to infiltrate melanoma tumors due to chemokines and other soluble signaling molecules such as CCL1 and CCL22. Once Tregs accumulate inside melanoma tumors, they generate an immunosuppressive microenvironment in a contact-dependent and contact-independent manner. IL-10 secretion and use of the CTLA-4 pathway were observed to be the most well characterized modes of suppression but other mechanisms are still being discovered. Clinicians can take advantage of new therapeutics to modulate the activity of Tregs. Exogenous administration of antibodies that bind to CTLA-4, PD-1, CCR4 and other receptors and molecules can prevent Treg development and action. Preventing Tregs from carrying out their suppressive function may allow other elements of the immune system, such as CD8+ TCs, to target and destroy melanoma cells. Clinicians can also measure the relative abundance of Tregs or use the ratio of effector TCs (Teff) and Tregs to predict patient outcomes and survival. More research is needed to determine that precise mechanisms of Treg infiltration and accumulation within the tumor and the mode of Treg suppression. This paper finds that there is no standard Treg identification marker. This can lead to aberrant results and failures such as the inability to distinguish Tregs from melanoma cells that also express Treg-like markers or a failure to identify other Treg subtypes. Lack of consensus also extends to the prognostic value of Tregs due, in part, to small sample sizes and the inability to accurately identify Tregs in vivo. Future research must focus on Treg identification, action, and the elucidation of therapeutic mechanisms. These future studies will ensure that clinicians have the correct information to choose the proper melanoma treatment that will target the specific Treg populations found within patients’ melanoma tumors.