The thyroid status reprograms T cell lymphoma growth and modulates immune cell frequencies

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 94; no. 4; pp. 417 - 429
• Main Authors: Sterle, H. A., Barreiro Arcos, M. L., Valli, E., Paulazo, M. A., Méndez Huergo, S. P., Blidner, A. G., Cayrol, F., Díaz Flaqué, M. C., Klecha, A. J., Medina, V. A., Colombo, L., Rabinovich, G. A., Cremaschi, G. A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2016; Springer Nature B.V
• Subjects: Animals; Antitumor activity; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; CD19 antigen; CD8 antigen; Cell cycle; Cell Line; Cell Proliferation - drug effects; Cytotoxicity; Disease Models, Animal; Female; Human Genetics; Hyperthyroidism; Hyperthyroidism - metabolism; Hypothyroidism; Hypothyroidism - metabolism; Immunomodulation; Inoculation; Internal Medicine; Lymph nodes; Lymphocyte Count; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, T-Cell - complications; Lymphoma, T-Cell - immunology; Lymphoma, T-Cell - metabolism; Lymphoma, T-Cell - pathology; Metastases; Metastasis; Mice; Molecular Medicine; Neoplasm Metastasis; Original Article; Phenotypes; Solid tumors; Spleen; Subpopulations; Suppressor cells; T-cell lymphoma; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Thyroid; Thyroid Diseases - complications; Thyroid Diseases - metabolism; Thyroid gland; Thyroid hormones; Thyroid Hormones - metabolism; Thyroid Hormones - pharmacology; Tumor Burden; Tumor Microenvironment - immunology; Tumor-infiltrating lymphocytes; Tumors; γ-Interferon; Thyroid hormones; Proliferation; Antitumor immune response; T cell lymphoma; Apoptosis
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-015-1363-2

In spite of considerable evidence on the regulation of immunity by thyroid hormones, the impact of the thyroid status in tumor immunity is poorly understood. Here, we evaluated the antitumor immune responses evoked in mice with different thyroid status (euthyroid, hyperthyroid, and hypothyroid) that developed solid tumors or metastases after inoculation of syngeneic T lymphoma cells. Hyperthyroid mice showed increased tumor growth along with increased expression of cell cycle regulators compared to hypothyroid and control tumor-bearing mice. However, hypothyroid mice showed a higher frequency of metastases than the other groups. Hyperthyroid mice bearing tumors displayed a lower number of tumor-infiltrating T lymphocytes, lower percentage of functional IFN-γ-producing CD8 + T cells, and higher percentage of CD19 + B cells than euthyroid tumor-bearing mice. However, no differences were found in the distribution of lymphocyte subpopulations in tumor-draining lymph nodes (TDLNs) or spleens among different experimental groups. Interestingly, hypothyroid TDLN showed an increased percentage of regulatory T (Treg) cells, while hyperthyroid mice displayed increased number and activity of splenic NK cells, which frequency declined in spleens from hypothyroid mice. Moreover, a decreased number of splenic myeloid-derived suppressor cells (MDSCs) were found in tumor-bearing hyperthyroid mice as compared to hypothyroid or euthyroid mice. Additionally, hyperthyroid mice showed increased cytotoxic activity, which declined in hypothyroid mice. Thus, low levels of intratumoral cytotoxic activity would favor tumor local growth in hyperthyroid mice, while regional and systemic antitumor response may contribute to tumor dissemination in hypothyroid animals. Our results highlight the importance of monitoring the thyroid status in patients with T cell lymphomas. Key messages T cell lymphoma phenotype is paradoxically influenced by thyroid status. Hyperthyroidism favors tumor growth and hypothyroidism rises tumor dissemination. Thyroid status affects the distribution of immune cell types in the tumor milieu. Thyroid status also modifies the nature of local and systemic immune responses.