1. Human leukocyte antigen (HLA) is a polymorphic cell-surface protein, and each individual has a unique combination of HLAs. HLAs on cancer cells present neoantigens to T cells [1–3]. This process...

Background Immune-related adverse events associated with immune checkpoint therapy cause autoimmune disease-like symptoms. People who carry specific genotypes or haplotypes of human leucocyte antigen (HLA) are known to be predisposed to develop autoimmune diseases including narcolepsy. Immunotherapy could be a trigger to develop narcolepsy in predisposing HLA positive patients. Case presentation A 66-year-old woman with stage IVB endometrial carcinosarcoma experienced daytime sleepiness and temporary muscle weakness 14 days after the administration of an immune checkpoint inhibitor, pembrolizumab. These were consistent with the main symptoms of narcolepsy with cataplexy. This patient carried a highly predisposing HLA haplotype for narcolepsy; HLA-DQB1*06:02, DRB1*15:01, DQA1*01:02 and DRB5*01:01:01. A hypocretin-1/orexin-A concentration in the patient’s cerebrospinal fluid was low at 9.6 pg/mL in ELISA, and 155.5 pg/mL in radioimmunoassay that was below the normal level of 200 pg/mL. Therefore, she was diagnosed with narcolepsy tentatively according to the International Classification of Sleep Disorders, third edition diagnostic criteria for narcolepsy. The onset of narcolepsy in the 60s is very rare, and narcoleptic symptoms in our patient were likely to be caused by pembrolizumab. Conclusions This case suggests that treatment with immune checkpoint inhibitors potentially causes narcolepsy in genetically predisposed patients.

Neural precursor cell-expressed developmentally downregulated 4–1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor α. We evaluated whether the expression level of NEDD4 affected the outcome of breast cancer patients. We performed a retrospective cohort study enrolling 143 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer. Of the 66 patients with high NEDD4 mRNA levels (high NEDD4 group) and 77 patients with low NEDD4 mRNA levels (low NEDD4 group), 98.4% and 96.1%, respectively, of the patients had received neoadjuvant/adjuvant hormone therapy. Disease-free survival and overall survival were significantly longer in the low NEDD4 group than in the high NEDD4 group (p = 0.048 and p = 0.022, respectively). Western blotting revealed a high expression of estrogen receptor α in the NEDD4-knockdown culture cells. The proliferation of NEDD4-knockdown cells treated with tamoxifen or estradiol deprivation was suppressed, compared with that of NEDD4-expressing cells. Knockdown of NEDD4 in breast cancer cells induced the accumulation of estrogen receptor α and increased sensitivity to hormone therapy. In summary, this mechanism may lead to a better prognosis in hormone receptor-positive breast cancer patients with a low expression of NEDD4.

Background: Neural precursor cell expressed developmentally downregulated 4-1 (NEDD4) is an E3 ligase that leads to the degradation of proteins including estrogen receptor a (ER). The E3 ligase can be a predictive marker of response to hormone therapy. We evaluated whether the expression level of NEDD4 affects the prognosis of hormone receptor-positive breast cancer patients. To support our clinical results, the association of NEDD4 with ER in breast cancer cells was studied.Methods: We performed a retrospective cohort study enrolling 145 patients with hormone receptor-positive HER2-negative breast cancer with pathological stage 0–II. Their expression levels of NEDD4 mRNA were measured, and disease-free survival (DFS) and overall survival (OS) were evaluated. Additionally, we knocked down NEDD4 in ER-positive breast cancer cells, MCF-7. We evaluated the expression level of ER in the cells and sensitivity to hormone therapy.Results: Mean follow-up time was 6.2 years. Of 67 patients with high NEDD4 levels (high NEDD4 group) and 78 patients with low NEDD4 levels (low NEDD4 group), 97.0% and 94.9% of the patients received neoadjuvant/adjuvant hormone therapy, respectively. The hormone therapy included aromatase inhibitors and tamoxifen. DFS and OS of the low NEDD4 group were significantly longer than the high NEDD4 group (p = 0.049 and p = 0.023). Western blot revealed high ER expression in NEDD4 knockdown cells. Proliferation of NEDD4 knockdown cells without estradiol stimulation as a simulation of the aromatase inhibitor therapy was suppressed to 53.6% of that with estradiol stimulation, whereas proliferation of NEDD4-expressing cells was suppressed to only 76.9%. Proliferation of NEDD4 knockdown cells with exposure to estradiol and hydroxytamoxifen was suppressed to 57.9% of that without exposure to hydroxytamoxifen. In contrast, proliferation of NEDD4-expressing cells was suppressed to only 73.3%. Thus, these simulations of hormone therapy showed a significant decrease in proliferation of NEDD4 knockdown cells.Conclusion: Knockdown of NEDD4 in ER-positive breast cancer cells resulted in ER accumulation and high-sensitivity to hormone therapy. Hormone receptor-positive breast cancer patients with low expression of NEDD4 had favorable DFS and OS.