Abstract LB-347: Thyroid cancer immunoediting by regulatory double negative (DN) T cells.

Thyroid cancer is usually surrounded by significant numbers of immune reactive cells. Tumor associated lymphocytes as well as lymphocytic infiltration organized in germinal centers (chronic lymphocytic thyroiditis or Hashimoto thyroiditis) are frequently mentioned in pathology reports of patients operated for thyroid cancer. The nature of this lymphocytic reaction in not well understood. Evidently, the fact that cancer can survive in this adverse environment speaks for immune regulation. Suppression of immune responses by regulatory T cells (Tregs) is critical for the induction and maintenance of self-tolerance. Tregs have been shown to be involved in downregulating immune responses in autoimmunity and tumor immunity. A variety of T-cell subsets possess immunoregulatory properties but the best studied is the classic CD4+CD25+Foxp3+ Treg. Other inducible Tregs such as T-regulatory type 1 (Tr1) cells, T-helper 3 (Th3) cells, CD8+CD28— T cells, and TCR-αβ+ CD4—CD8— double-negative (DN) T cells also show the ability to inhibit immune responses. Here we characterized the lymphocytic infiltration that accompanies thyroid cancer and compared it to that present in autoimmune thyroid disease. Ex-vivo aspirations of human thyroid glands affected by both diseases and controls were carried out. Lymphocytes were isolated and either analyzed immediately by flow cytometry or placed in culture and stimulated 24 hours after. We mainly found that DN T cells are significantly more abundant in thyroid cancer than in thyroid autoimmune disease. Although Tregs are also present, DN T cells are the dominant cell type associated with thyroid cancer. DN T cells are 10 times more abundant than classic Tregs. Furthermore, upon PMA/Ionomycin stimulation, the DN T cells associated with the cancer remain unchanged while the few (5%) DN T cells associated with thyroid autoimmune disease increase in numbers (20%). CD25 (alpha chain of the IL2 receptor and maker for activation) expression on DN T cells in the setting of thyroid cancer remains unchanged after stimulation. CD25 expression on DN T cells in the setting of thyroid autoimmune disease also remains unchanged which suggests that the increase in the absolute number of DN T cells is at the expense of inactivated DN T cells. We concluded that in the setting of thyroid cancer, DN T cells appear to suppress tumor immunity. Moreover, DN T cells were also able to downregulate proliferation and cytokine production of highly activated effector T cells coexisting at the tumor site. In contrast, in thyroid autoimmunity, DN T cells were barely present and only proliferated at the expense of inactivated cells upon stimulation in-vitro. Together, these data suggest that thyroid cancer associated DN T cells might regulate proliferation and effector function of T cells and thereby contribute to tumor tolerance and active avoidance of tumor immunity. Citation Format: Shahnawaz Imam, Juan Carlos Jaume. Thyroid cancer immunoediting by regulatory double negative (DN) T cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-347. doi:10.1158/1538-7445.AM2013-LB-347 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.