Autoimmune thyroiditis has a protective role on papillary thyroid cancer: Insights from a new mouse model

The relationship between papillary thyroid cancer (PTC) and autoimmune thyroiditis remains controversial. To gain mechanistic insights, we developed a mouse model by combining three strains: BRAFv600E knock-in and TPO-CRE-ER transgenic to induce PTC upon tamoxifen injection, and NOD.H2h4 congenic to induce thyroiditis upon iodine administration. A total of 113 mice of the desired genotype (BRAF mutant homozygous, CRE transgenic hemizygous on the NOD.H2h4 background) were generated and separated into three cohorts. Mice in cohort 1 (n = 50) were observed until death after tamoxifen and/or iodine treatment(s) to define the natural history of PTC and thyroiditis, while mice incohorts 2 and 3 (n = 63) were sacrificed at a fixed time point after treatment (16 weeks after the first tamoxifen injection). Each cohort comprised six experimental groups: in Group 1 (n = 22) tamoxifen and iodine were begun simultaneously, in Group 3 (n = 20) tamoxifen followed iodine treatment, and in Group 5 (n = 23) only tamoxifen was used. Each of these groups had its own control, (defined as group 2, 4, and 6 respectively) where no tamoxifen was given. In addition to survival, outcome measures included monthly assessment of thyroid ultrasound, thyroid function (TSH and T4), thyroglobulin and thyroperoxidase antibodies, and thyroid histopathology and flow cytometry at the time of sacrifice. In mice observed through their life time (cohort 1), tamoxifen induced the development of PTC in all three groups (1, 3, and 5) but with significantly different aggressiveness. While groups 1 and 5 died at 36 weeks of age, mice with preceding thyroiditis (group 3) died much later (after one year of age, P < 0.001). In mice sacrificed at 16 weeks post tamoxifen, the incidence of PTC was significantly smaller in group 3 than groups 1 and 5 (P < 0.0001), again indicating a ‘beneficial’ effect of pre-existing thyroiditis. Thyroglobulin antibodies developed, as expected, in mice treated with iodine and persisted throughout the observation time, but did not distinguish between the outcomes. On the contrary, thyroperoxidase antibodies developed later but remained elevated only in mice developing PTC. Lymphocytic infiltration in PTC lesions was greater in group 3 than group 1 (P = 0.002) or 5 (P = 0.04), and featured a unique expansion of CD8 + effector memory T cells (P = 0.009). Overall, the study shows that pre-existing thyroiditis protects from PTC aggressiveness and progression, a protection that, however, disappears when thyroiditis and PTC are induced synchronously.