Homozygous deletion of the HLA-B gene as an acquired-resistance mechanism to nivolumab in a patient with lung adenocarcinoma: a case report

Abstract

Immune checkpoint inhibitors (ICIs) have greatly improved the treatment of advanced non-small-cell lung cancer, including lung adenocarcinoma (LUAD). Patients treated with ICIs can have long-term clinical outcomes; however, acquired resistance to ICI therapy has been frequently observed. To date, little is known about the underlying mechanisms. In this study, we report the case of a male smoker with metastatic LUAD who initially received multi-line radiotherapy and chemotherapy and achieved stable disease (SD) for almost 10 years. The patient was treated with nivolumab for about 15 months. However, the disease later progressed rapidly. A genetic profile of the patient revealed the homozygous deletion of the human leukocyte antigen (HLA)-B gene, which may have conferred the acquired resistance. Our study is the first to describe the homozygous deletion of the HLA-B gene as an acquired-resistance mechanism to programmed cell death protein 1 (PD-1) blockade in a patient with LUAD. This evidence suggests that tumor cells can selectively lose HLA-A, B, and C to survive under strong immune pressure. This discovery enriches and develops our understanding of the mechanism of drug resistance in ICI therapy in LUAD. However, further investigations are urgently needed to be conducted to determine how this resistance can be overcome.