Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor–induced secondary adrenal insufficiency

Seiichi Yano, Kenji Ashida, Ryuichi Sakamoto, Chihiro Sakaguchi, Masatoshi Ogata, Kengo Maruyama, Shohei Sakamoto, Munehiko Ikeda, Kenji Ohe, Shoko Akasu, Shimpei Iwata, Nobuhiko Wada, Yayoi Matsuda, Yoichi Nakanishi, Masatoshi Nomura, Yoshihiro Ogawa

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)198-203
Number of pages6
JournalEuropean Journal of Cancer
Publication statusPublished - May 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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