Seiichi Yano1, Kenji Ashida2, Ryuichi Sakamoto1, Chihiro Sakaguchi1, Masatoshi Ogata1, Kengo Maruyama1, Shohei Sakamoto1, Munehiko Ikeda3, Kenji Ohe4, Shoko Akasu5, Shimpei Iwata5, Nobuhiko Wada5, Yayoi Matsuda1, Yoichi Nakanishi6, Masatoshi Nomura7, Yoshihiro Ogawa1. 1. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 2. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan. Electronic address: ashida@med.kurume-u.ac.jp. 3. Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan. 4. Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. 5. Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan. 6. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 7. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.
Abstract
BACKGROUND: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. PATIENTS AND METHODS: We enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. RESULTS: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). CONCLUSIONS: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.
BACKGROUND: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. PATIENTS AND METHODS: We enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. RESULTS: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). CONCLUSIONS: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.
Authors: Melissa G Lechner; Mandy I Cheng; Anushi Y Patel; Aline T Hoang; Natalie Yakobian; Michael Astourian; Marissa S Pioso; Eduardo D Rodriguez; Ethan C McCarthy; Willy Hugo; Trevor E Angell; Alexandra Drakaki; Antoni Ribas; Maureen A Su Journal: J Immunol Date: 2022-07-11 Impact factor: 5.426