Immune checkpoint inhibitory (ICI) therapy represents a novel approach in a variety of cancers, with impressive survival benefit. With ICIs, however, a new spectrum of immune related adverse events (irAE) including life threatening hypohysitis has emerged. This autopsy study aimed to investigate inflammatory cells, PD-1 and PD-L1 expression in cases of patients who developed hypophysitis and involvement of other organs.

We analysed 6 patients, who were treated with ICIs and developed hypophysitis. Two received an additional MAP-kinase inhibitor, MEK-inhibitor and cytotoxic chemotherapy. Besides the pituitary gland, all investigated adrenal glands (5/5) were affected; three cases had other organs involved (liver (2/6), thyroid (2/6), lung (1/6), myocardium (1/6), colon (1/6). The inflammatory cells of involved organs were further specified and PD1 and PDL-1 expression was analyzed using immunohistochemistry. We observed that patients treated with ICIs alone showed T-cell predominant lymphocytic infiltrates, whereas patients receiving additional therapies demonstrated an increase in B- and T-lymphocytes. Surprisingly, the dominant inflammatory population was not T-cell, but type 2 macrophages. CD25 positive T-regs were sparse or absent.

Our study suggests that T cell activation is only partially responsible for irAE. ICI therapy interaction with CTLA-4, PD-1 and PDL-1 in type 2 macrophages appears to result in disturbance of their control. Furthermore, depletion of T-regs seems to contribute significantly. Our findings with simultaneous pituitary and adrenal gland involvement underlines the systemic involvement as well as the importance of monitoring cortisol levels to avoid potentially life threatening hypocortisolism.

免疫检查点抑制 (ICI) 疗法代表了一种治疗多种癌症的新方法，具有显着的生存益处。然而，对于 ICI，出现了一系列新的免疫相关不良事件 (irAE)，包括危及生命的垂体炎。这项尸检研究旨在调查患有垂体炎和其他器官受累的患者的炎症细胞、PD-1 和 PD-L1 表达。

我们分析了 6 名接受 ICI 治疗并出现垂体炎的患者。其中两人接受了额外的 MAP 激酶抑制剂、MEK 抑制剂和细胞毒性化疗。除脑垂体外，所有受调查的肾上腺（5/5）均受到影响；3例有其他器官受累（肝（2/6）、甲状腺（2/6）、肺（1/6）、心肌（1/6）、结肠（1/6），受累器官炎症细胞进一步增多使用免疫组织化学分析 PD1 和 PDL-1 表达。我们观察到，单独接受 ICI 治疗的患者表现出 T 细胞占主导地位的淋巴细胞浸润，而接受额外治疗的患者表现出 B 和 T 淋巴细胞的增加。令人惊讶的是，占主导地位的炎症群体不是 T 细胞，而是 2 型巨噬细胞。CD25 阳性 T-regs 稀疏或不存在。

我们的研究表明 T 细胞活化只是 irAE 的部分原因。ICI 治疗与 2 型巨噬细胞中的 CTLA-4、PD-1 和 PDL-1 的相互作用似乎导致它们的控制受到干扰。此外，T-regs 的消耗似乎有很大贡献。我们发现垂体和肾上腺同时受累，强调了全身受累以及监测皮质醇水平以避免可能危及生命的皮质醇减退症的重要性。