Clinical implications of immune checkpoint markers and immune infiltrates in patients with thymic neuroendocrine neoplasms.

The potential response of immune checkpoint blockade (ICB) in thymic neuroendocrine neoplasms (T-NEN) is largely unknown and full of great expectations. The expression of immune checkpoint molecules and immune infiltrates greatly determine the response to ICB. However, studies regarding the immune landscape in T-NEN are scarce. This work was aimed to characterize the immune landscape and its association with clinical characteristics in T-NEN. The expression of programmed cell death protein 1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1), and the density of tumor-infiltrating lymphocytes (TILs), monocytes, and granulocytes were determined by immunohistochemical (IHC) staining on tumor tissues from T-NEN. Immune landscapes were delineated and correlated with clinicopathological factors. We found that T-NEN with increased immune cell infiltration and enhanced expression of PD-1/PD-L1 tended to have restricted tumor size and less metastases. A higher density of CD8 TILs was associated with a significantly lower rate of bone metastasis. In addition, we presented three cases of T-NEN who progressed after multiple lines of therapies and received ICB for alternative treatment. ICB elicited durable partial responses with satisfactory safety in two patients with atypical carcinoid, but showed resistance in 1 patient with large cell neuroendocrine carcinoma. This innovative study delineated for the first time the heterogeneous immune landscape in T-NEN and identified CD8 TILs as a potential marker to predict bone metastasis. An "immune-inflamed" landscape with the presence of TILs predominated in T-NEN, making T-NEN a potentially favorable target for ICB treatment. Further judicious designs of "tailor-made" clinical trials of ICB in T-NEN are urgently needed.