ODP355 The analysis of tumor infiltrative lymphocytes in corticotroph adenomas and its relation to hormonal status
Authors: Fukuoka Hidenoi , Itoh Tomoo , Kanie Keitaro , Kanzawa Maki , Ogawa Wataru , Shichi Hiroki , Yamada Shozo , Yamamoto Masaaki 
Published: November 2022

Abstract

Background
Corticotrophs are a well-known tissue susceptible to cytotoxicity by lymphocytes, as seen in autoimmune hypophysitis, suggesting that immunological approach may be one of the therapeutic strategies for ACTH-producing adenomas. However, the efficacy of immune therapy for general ACTH-producing adenomas remains unclear. And cortisol levels expected to affect the tumor microenvironment (TME).

Objectives
To clarify whether ACTH-producing adenomas are sensitive to immunotherapy and if this approach can be a potential treatment for these challenging tumors.

Methods
TME was examined by immunostaining using pituitary adenomas specimens. This study consists of two phases: In phase 1, TME of ACTH-producing adenomas (n=29) was analyzed by comparing with GH-producing pituitary adenomas (GHomas) (n=10) and nonfunctioning pituitary adenomas (NPAs) derived from gonadotrophs origin (Gnomas) (n=10). In phase 2, corticotroph adenomas were divided into three groups that were considered to be at different cortisol exposure; naïve ACTH-producing adenomas (Naïve, n=29), treatment with metyrapone (Met, n=13), and silent corticotroph adenomas (SCAs) (n=12). These TME were analyzed and compared. To detect T-lymphocytes and M2 macrophages, antibodies to CD3, 4, or 8, and CD163 were used, respectively. The association between TME and patients’ background data including urinary free cortisol levels were analyzed.

Results
Phase 1: Tumor infiltrating lymphocytes (TILs) evaluated by CD3 + cells inACTH-producing adenomas were less than those in the GHomas (p&lt;0. 01) and lower tendency compare to Gnomas (p=0. 05). Among them, CD8 + cells in ACTH-producing adenomas were less than both (p&lt;0. 01, p&lt;0. 01, respectively). CD163 + cells were widely distributed in ACTH-producing adenomas but less than Gnomas (p&lt;0. 01). The number of CD163 + cells were not associated with tumor aggressiveness or invasiveness in ACTH-producing adenomas. Phase 2: First, SCAs, NPAs from corticotroph origin were compared to Gnomas, showing that less CD8 + cells were detected in SCAs (p&lt;0. 01), suggesting low CD8 + cells were common feature of corticotroph adenomas regardless of cortisol level. Among 3 groups of different cortisol exposure, CD4 + cells were higher both in Met and SCAs than in Naïve (p&lt;0. 01, p=0. 01, respectively), while CD8+ cells were not altered. In contrast, the number of CD163+ cells were lower in Met than Naïve (p&lt;0. 01), suggesting the association between cortisol levels and the number of CD163 + cells.

Conclusions
We revealed for the first time that low TILs are common features among corticotroph adenomas regardless cortisol levels. Moreover, the CD4 + cells but not CD8 + cells were higher in tumors with low cortisol status, suggesting induction of CD8 + cells are required for the immune therapy to corticotroph adenomas. Regarding with CD163 + cells, no association with tumor behavior was shown rather related to cortisol exposure status.
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