To study the immunological processes involved in sporadic or Multiple Endocrine Neoplasm (MEN2) related Medullary Thyroid Carcinoma (MTC) and its implications in systemic immunity and tumoral microenvironment

Abstract

Our group has been studying the microenvironment of thyroid tumors for several years (186-192); in this period, we acquired maturity in the investigation of systemic or local immunological processes in patients with papillary thyroid carcinoma. This experience and knowledge motivated us to study the same phenomenon in patients with medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2 (MEN2). In addition to influencing MTC genesis, the RET gene appears to have a role in balancing the immune response of mammals (193,194), as it is constitutively expressed in some hematopoietic tissues and lymphoid organs, such as the thymus, spleen, and lymph nodes (194-198). When abundantly expressed, RET is able to induce the expression of pro-inflammatory cytokines and chemokines, suggesting that it contributes to the regulation of immune system homeostasis (199). Furthermore, RET activation in peripheral blood mononuclear cells is capable of modulating the expression of several genes of innate and adaptive immunity (200). Additionally, RET stimulates the secretion of growth factors, which induce the production of chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1) and pro-inflammatory cytokines (IL-1b, IL-6 and IL-8) (199). A study with transfected with mutations NIH-3T3 cells causing MEN2A (RET with gain of function C609Y and C634R) showed that they were capable of activating the antitumor immune response through proliferation, migration and cytotoxicity of "natural killer" (NK) lymphocytes stimulating pathways (201). Similarly, mutations in the RET gene have been found to activate the production of adjacent to the tumor stroma-modifying oncoproteins (202). Other investigators have shown that MTC-derived tissues have an inflammatory infiltrate permeated by CD8+ T cells and few myeloid cells with an exhaustion phenotype, a process characterized by the progressive loss of functions of some immune system cells (203); in that study, PD-L1 expression on tumor-infiltrating lymphocytes was rare, whereas adhesion molecules such as CD155 and CD47 on lymphocytes were abundantly expressed, suggesting that MTC had an immunogenic phenotype (203). However, these authors did not differentiate tumoral tissues from sporadic TCM or from patients with MEN2. Furthermore, the authors did not compare the immunological characteristics with the clinical course, compromising the immediate applicability of these findings. The balance of molecular modifications enriched by the mixture of cells of the immune system is what leads to the establishment of a microenvironment that can be pro-tumor or antitumor. These mechanisms should be explored for the development of immunotherapies and new prognostic tools in the context of MTC. Thus, a microenvironment enriched with immune cells activated with antitumor effector mechanisms would be associated with better prognostic characteristics. On the other hand, a microenvironment enriched with immune cells with an exhaustion phenotype could promote immune escape and be associated with worse clinical outcomes. Our studies will be able to define which patients have tumor-infiltrating lymphocytes that are exhausted or anergic. Identifying these patients would help to select the best candidates for immunotherapy with antibodies that inhibit immunological checkpoints.