Antecedent viral immunization and efficacy of immune checkpoint blockade: An extensive serum antibody profile to predict outcomes in non-small cell lung cancer

Introduction Immune checkpoint blockers (ICBs) revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC) but only a fraction of them obtain a response, and clinical benefit from these treatments is often difficult to predict. The aim of our study is to unveil the potential implications of antibody response to previous viral infections in predicting response to ICBs in patients with NSCLC. Methods Sera from patients treated with ICBs alone, chemotherapy (CT) or a combination of CT-ICBs were analyzed with VirScan (CDI Labs, USA), a high-throughput method that comprehensively analyzes epitope-level antiviral IgG antibodies via programmable phage display and immunoprecipitation sequencing. Total number of unique positive peptides (tUP) was defined as the total number of non-overlapping positive "is a hit"peptides for each patient. Results Overall, 387 patients were included. Of them, 129 were treated with ICBs alone, 66 with CT-ICBs and 195 with CT alone. 90 out of 129 patients treated with ICBs alone received ICBs as a subsequent line of treatment, while CT-ICBs and CT were administered as upfront therapies. A higher tUP was correlated with improved overall survival in patients treated with ICBs, and confirmed in the multivariate model (HR 0.43, 95% CI 0.24, 0.79, p=0.006), while it was not in those treated with CT-ICBs (p=0.8) and CT alone (p=0.1). tUP was not correlated with programmed death-ligand 1 (PD-L1) expression, while at the transcriptome level it was correlated with several immune-related pathways, particularly involving B cells. Conclusion A higher number of viral peptides recognized by serum antibodies might reflect increased immune fitness, resulting in improved outcomes in ICBs treated patients with NSCLC.