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

• Published in: Endocrinology (Philadelphia) 2024-02, Vol.165 (4)
• Main Authors: Kanzawa, Maki, Shichi, Hiroki, Kanie, Keitaro, Yamamoto, Masaaki, Yamamoto, Naoki, Tsujimoto, Yasutaka, Bando, Hironori, Iguchi, Genzo, Kitano, Shigehisa, Inoshita, Naoko, Yamada, Shozo, Ogawa, Wataru, Itoh, Tomoo, Fukuoka, Hidenori
• Format: Article
• Language: English
• Subjects: ACTH-Secreting Pituitary Adenoma - pathology; Adenoma - pathology; Brain tumors; CD163 antigen; CD4 antigen; CD8 antigen; Cell culture; Cell size; Corticotrophs; Cortisol; Cytotoxicity; Dimensional analysis; Hormones; Humans; Hydrocortisone; Immune checkpoint inhibitors; Immune system; Immunology; Immunotherapy; Infiltration; Lymphocytes; Lymphocytes T; Macrophages; Metastases; Pituitary; Pituitary (anterior); Pituitary Neoplasms - pathology; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/endocr/bqae016

Abstract 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: Naïve (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 Naïve, Met, and SCA. The number of CD4+ cells, but not CD8+ cells, was higher in both Met and SCA than in Naïve. 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.