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

Maki Kanzawa, Hiroki Shichi, Keitaro Kanie, Masaaki Yamamoto, Naoki Yamamoto, Yasutaka Tsujimoto, Hironori Bando, Genzo Iguchi, Shigehisa Kitano, Naoko Inoshita, Shozo Yamada, Wataru Ogawa, Tomoo Itoh, Hidenori Fukuoka
Endocrinology, Volume 165, Issue 4, April 2024, bqae016
https://doi.org/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.

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