Effects of the Cortisol Milieu on Tumor-Infiltrating Immune Cells in Corticotroph Tumors

Context: Corticotrophs are susceptible to lymphocyte cytotoxicity, as seen in hypophysitis, suggesting that an immunological approach may be a potential strategy for corticotroph-derived tumors. Objective: We aimed to clarify whether corticotroph tumors that induce hypercortisolemia (ACTHomas) could be targets for immunotherapy. Methods: Tumor-infiltrating immune cells were immunohistochemically analyzed. ACTHomas were compared with other pituitary tumors, and further divided into 3 different cortisol-exposed milieus: Naive (ACTHomas without preoperative treatment), Met (ACTHomas with preoperative metyrapone), and SCA (silent corticotroph adenomas). A 3-dimensional cell culture of resected tumors was used to analyze the effects of immune checkpoint inhibitors. Results: The number of tumor-infiltrating lymphocytes (TILs) was low in ACTHomas. Among these, the number of CD8+ cells was lower in ACTHomas than in both somatotroph and gonadotroph tumors (both P < .01). Then we compared the differences in TILs among Naive, Met, and SCA. The number of CD4(+) cells, but not CD8(+) cells, was higher in both Met and SCA than in Naive. Next, we investigated tumor-associated macrophages, which could negatively affect T cell infiltration. The numbers of CD163(+) and CD204(+) cells were positively associated with cortisol levels. Moreover, tumor size was positively correlated with the number of CD204(+ )cells. Conclusion: We found the possibility that ACTHomas were immunologically cold in a cortisol-independent manner. In contrast, the tumor infiltration of CD4(+) cells and M2-macrophages were associated with the cortisol milieu. Future studies are needed to validate these results and develop effective immunotherapy while considering the cortisol milieu.