Abstract. Although antibodies targeting the immune check‐ point protein programmed death‐1 (PD‐1) exert therapeutic effects in patients with primary or metastatic non‐small cell

Although antibodies targeting the immune check‐ point protein programmed death‐1 (PD‐1) exert therapeutic effects in patients with primary or metastatic non‐small cell lung cancer (NSCLC), the majority of patients exhibit partial or complete resistance to anti‐PD1 treatment. Thus, the aim of the present study was to identify reliable biomarkers for predicting the response to anti‐PD‐1 therapy. The present study analyzed tumor specimens isolated from 24 patients (13 with primary and 11 with metastatic NSCLC) prior to treatment with approved PD1‐targeting antibodies. The expression profile of 395 immune‐related genes was examined using RNA immune‐oncology panel sequencing. The results demonstrated that six immune‐related differently expressed genes (DEGs), including HLA‐F‐AS1, NCF1, RORC, DMBT1, KLRF1 and IL‐18, and five DEGs, including HLA‐A, HLA‐DPA1, TNFSF18, IFI6 and PTK7, may be used as single biomarkers for predicting the efficacy of anti‐PD‐1 treatment in patients with primary and with metastatic NSCLC, respectively. In addition, two DEG sets comprising either six (HLA‐F‐AS1, NCF1, RORC, DMBT1, KLRF and IL‐18) or two (HLA‐A and TNFSF18) DEGs as potential combination biomarkers for predicting the efficacy of anti‐PD‐1 therapy in patients with NSCLC. Patients with a calculated expression level of the DEG sets >6.501 (primary NSCLC) or >6.741 (metastatic NSCLC) may benefit from the anti‐PD‐1 therapy. Overall, these findings provided a basis for the identification of additional biomarkers for predicting the response to anti‐PD‐1 treatment. Introduction According to global cancer statistics in 2018, lung cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality, accounting for 18.4% of total cancer deaths (1). Non‐small cell lung cancer (NSCLC) accounts for 80‐85% of all cases of lung cancer (2). The optimal therapy for improving survival rates of NSCLC patients depends on an early diagnosis at stage I and II when surgical resection remains a feasible and consistent option (3). However, surgery is not an effective therapy for patients with an advanced or metastatic NSCLC; instead, chemotherapy, radiotherapy and targeted therapy (e.g. targeting epidermal growth factor receptor and vascular endothelial growth factor) can be used alone or in combination (4,5). Monoclonal antibodies blocking immunological checkpoints, also termed immune checkpoint inhibitors (ICIs), have become promising therapeutic options for patients diagnosed with advanced NSCLC with or without metastasis (6). Among them, anti‐programmed death‐1 (PD‐1) monoclonal antibodies have been widely used for treating advanced NSCLC (7‐10). Antibodies targeting PD‐1 prevent tumor cells from escaping immune‐mediated destruction (11). The PD‐1 receptor is a vital immune checkpoint molecule expressed on activated T cells that mediates immunosuppres‐ sion (12). Binding of PD‐1 to its ligands (PD‐L1 and PD‐L2) on cancer cells suppresses T cells, resulting in evasion of the immune response (12). Anti‐PD‐1 antibodies bind to PD‐1 receptors to disrupt the inhibition of T cells by tumor cells, enhancing the antitumor effects of the immune system (12). Previous clinical trials, including CheckMate 017 (13) and 057 (14), KEYNOTE‐010(9) and KN‐024 (10), have demon‐ strated that compared with docetaxel, anti‐PD‐1 antibodies significantly prolonged the overall survival and had a favor‐ able safety profile in patients with advanced NSCLC. Despite the prominent therapeutic effects of anti‐PD‐1 monoclonal antibodies on patients with advanced NSCLC, only a limited fraction of patients benefit from this immunotherapeutic agent (15). Therefore, developing reliable methods to predict the efficacy of anti‐PD‐1 monoclonal antibody in treating patients with advanced NSCLC may provide economic relief Immune‐related genes and gene sets for predicting the response to anti‐programmed death 1 therapy in patients with primary or metastatic non‐small cell lung cancer BOLIN CHEN1, MIN YANG2, KANG LI1, JIA LI1, LI XU1, FANG XU1, YAN XU1, DANDAN REN3, JIAO ZHANG3 and LIYU LIU1 1Thoracic Medicine Department 2, Cancer Hospital Affiliated to Xiangya Medical College, Central South University, Changsha, Hunan 410013; 2Department of Respiratory Disease, Hunan Children's Hospital, Changsha, Hunan 410007; 3Genecast Biotechnology Co., Ltd., Beijing 100089, P.R. China Received December 5, 2020; Accepted April 14, 2021 DOI: 10.3892/ol.2021. 12801 Correspondence to: Dr Liyu Liu, Thoracic Medicine Department 2, Cancer Hospital Affiliated to Xiangya Medical College, Central South University, 283 Tongzipo Road, Yuelu, Changsha, Hunan 410013, P.R. China E‐mail: lly12121212@163.com