Heterogeneity of Neoantigen Landscape Between Primary Lesions and Their Matched Metastases in Lung Cancer

Background: To investigate whether neoantigens identified from primary tumors are similar to their matched metastases in lung cancer. Methods: Primary lesions, matched metastases and peripheral blood were collected before systemic therapy. We used following major criteria for neoantigen identification: derived from tumor-specific mutations, fold change > 10 comparing to germline expression level, high predicted human leukocyte antigen (HLA) binding affinity (IC 50 < 500 nM) and peptide of 9-11 amino acids in length. Findings: 79 samples from 24 cases were identified, including 10 with liver metastasis (LM), 10 with brain metastasis (BM) and 4 with sole BM. A wide range of tumor neoantigen burden was identified in both primaries (median 214, range 54-2992) and metastases (median 178, range 34-2488). The counts, overall distribution pattern and predicted HLA binding affinity of neoantigens were similar between primaries and metastases. However, only a low percentage of shared neoantigens (presented in both primaries and metastases) was observed, which were mainly derived from single nucleotide variants and fusions. A variety of corresponding HLA alleles were observed and HLA-C*06:02 was found in 10 cases (50.0%). Additionally, neoantigen intratumor homogeneity with a low percentage of shared neoantigens was observed in sole BM. Interpretation: Although neoantigen landscape in terms of the number, type and predicted HLA binding affinity was found similar between primaries and metastases, the percentage of shared neoantigens is only modest, suggesting vaccine development based solely on primary tumor neoantigen may not offer optimal therapeutic outcome, and shared neoantigen needs to be seriously considered. Funding Statement: This study was supported in part by grants from the National Natural Science Foundation of China (No. 81772467, 81871865, 81874036 and 81972167), the Backbone Program of Shanghai Pulmonary Hospital (NO. FKGG1802), “Shuguang Program” supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission (No. 16SG18). Declaration of Interests: Henghui Zhang and Ji He is employee of Beijing Genecast Biotechnology Co., Beijing, China. Ying He and Renhong Tang are employee of Shanghai Hengrui Pharmaceutical Co. LTD, Shanghai, China. The other authors declare no potential conflict of interest. Ethics Approval Statement: The study protocol was approved by the Institutional Review Board of each center. Informed consent was obtained before sample collection. This study was conducted in accordance with the Declaration of Helsinki.