Dysfunction of natural killer cells mediated by PD-1 and Tim-3 pathway in anaplastic thyroid cancer

The survival rate of anaplastic thyroid cancer (ATC) remains about 7% to 14%. The natural killer (NK) cells are a critical component of antitumor immunity, and their composition and function in thyroid cancer patients are investigated in this study. In healthy controls and early stage thyroid cancer patients, >90% of circulating NK cells were CD56loCD16hi and fewer than 10% were CD56hiCD16hi/lo. However, the frequency of the CD56hiCD16hi/lo NK subset was significantly higher in more advanced thyroid cancer patients and further increased in ATC patients. Two members of the inhibitory KIR family, CD158a and CD158b, was significantly higher in CD56hiCD16hi/lo NK cells than in CD56loCD16hi NK cells, while NKG2D, an activator of NK cells, was significantly lower in CD56hiCD16hi/lo NK cells than in CD56loCD16hi NK cells. We also found that the CD56hiCD16hi/lo NK cells presented higher PD-1, higher Tim-3, and lower cytotoxicity against the human ATC cell line CAL-62, than the CD56loCD16hi NK cells. The expression of exhaustion markers and reduction in cytotoxicity was further exacerbated in more advanced thyroid cancer patients and in ATC patients. Interestingly, PD-1 and Tim-3 blockade was effective at reinvigorating both the more impaired CD56hiCD16hi/lo NK cells and the less impaired CD56loCD16hi NK cells from ATC patients. Together, our study identified a dysfunction of NK cells in more advanced thyroid cancer patients and ATC patients, and presented actionable targets for future development of immunotherapies in thyroid cancers.