Preconditioning of the immune system modulates the response of papillary thyroid cancer to immune checkpoint inhibitors.

backgroundThe response of solid tumors such as papillary thyroid cancer (PTC) to immune checkpoint inhibitors (ICIs) is highly variable. The biological basis of this variability remains unknown.

methodsTo test the hypothesis that preconditioning of the immune system modulates the therapeutic effect of ICIs, we used a murine model where PTC and iodine exacerbated thyroiditis (IET) can be induced in a temporally predictable fashion. A total of 122 mice were divided into 3 experimental groups. In the first one, named concomitant IET and PTC (No.=40), IET, and PTC were induced at the same time; in the second one, named pre-existing IET (No.=44), IET was induced prior to the induction of PTC; in the third one, named no IET (No.=38), only PTC was induced. Following disease induction, mice of each group were treated with anti-PD-1 antibody, anti-lymphocyte activation gene 3 antibody (anti-Lag3), anti-T-cell immunoglobulin and mucin domain 3 antibody (anti-Tim3), or IgG control. Ten weeks after the initial ICI injection, mice were sacrificed to collect the thyroid gland for histological analysis, to quantify the incidence and burden of PTC, and to perform high-throughput single-cell RNA sequencing of infiltrating CD45

resultsIn the concomitant IET and PTC group, ICI treatment reduced PTC incidence (p=0.002 comparing treatment with any ICI vs control), while it had no effect in the pre-existing IET and no IET groups. Single-cell sequencing of thyroidal CD45

conclusionsResponse to ICIs depends on the status of the immune system of the treated individual. Modulation of the immune system should be explored as a tool to improve response to ICIs in patients with PTC or other forms of cancer.