Analysis of the immune response in the microenvironment of medullary thyroid carcinoma: from the bench to clinical applications

Abstract

This project is linked to the ongoing thematic project 2021/02752-6, which aims to investigate the pathophysiological mechanisms of medullary thyroid carcinoma (MTC) in patients with multiple endocrine neoplasia type 2 (MEN2). MEN2 is a genetic disease with autosomal dominant inheritance characterized by associations of tumours of endocrine origin. MTC arises from calcitonin-producing thyroid parafollicular C cells derived from the neural crest and is the most important clinical manifestation of MEN2, being the main cause of death in patients. For localized MTC, the main treatment is total thyroidectomy with emptying of the central compartment; for disseminated disease, surgery is not related to cure. In view of this, the study of the tumor microenvironment and a better understanding of it may benefit the design of immune-mediated treatments in the future. Therefore, the aim of this study is to study the immunological processes involved in sporadic MTC and MEN2 by: (i) analyzing the transcriptomic profile in tissues from primary and metastatic MTC tumors using NanoString technology; (ii) analyzing the lymphocyte infiltration profile in the same tissues, correlating it with the clinical evolution of the patients; (iii) detailing the "ex vivo" lymphocyte expansion associated with the tumor. The results of our immunological studies will provide data that we will use in a comparative analysis of patients grouped according to the aggressiveness of their clinical presentation. The comparison will be made with the following groups: (i) 5 patients with sporadic MTC, (ii) 5 patients with MTC and MEN2 with very high risk mutations, 5 patients with MTC and MEN2 with high risk mutations and 10 patients with MTC and MEN2 with moderate risk mutations. We hope that the combination of immunological and genetic data can contribute to a better understanding of the tumor microenvironment in MTC, as well as possible therapeutic targets for this disease.