Baseline autoantibodies and treatment outcomes in metastatic melanoma treated with anti–PD-1 or ipilimumab combination immunotherapy.

Abstract

e21505 Background: B cells can exert both pro- and anti-tumor effects depending on the cancer type, disease stage, and the tumor microenvironment. They may enhance anti-tumor immunity through antigen presentation, antibody production that activates effector pathways, and the formation of tertiary lymphoid structures. However, the role of autoantibodies (AAbs) in predicting response to immune checkpoint inhibitors remains poorly understood. Methods: Baseline serum from 166 patients with stage IV melanoma who received either pembrolizumab (pembro, n=101) or ipilimumab plus nivolumab (ipi/nivo, n=65) was analyzed to identify AAbs associated with overall response rate (ORR), progression free (PFS) and overall survival (OS). AAbs were measured using an 832-antigen immuno-oncology array. Analyses were performed separately for each treatment group. AAbs associated with ORR were identified by Significance Analysis of Microarrays (SAM; d-score ≥1.8, p < 0.05). The proportional hazard ratio (HR) was calculated for AAbs associated with PFS and OS by Cox regression analysis (p<0.05). PFS and OS were measured from treatment initiation until progression and/or death. For each treatment and outcome, the 10 AAbs with the highest HR and p<0.05 were selected, prioritising overlapping markers. Results: In pembro-treated patients, AAbs to ECE1 and TNFRSF1B were positively associated with PFS and OS, whereas AAbs to DHFR and ACPP were negatively associated. ECE1 generates endothelin peptides that drive tumor growth and angiogenesis, and TNFRSF1B (TNFR2) supports immunosuppressive Treg activity in the TME. Anti-IL4R was associated with longer OS. In the ipi/nivo cohort, anti-TNFRSF10B was positively associated with ORR and PFS, while anti-PLEKHM2 was negatively associated. TNFRSF10B (DR5) mediates TRAIL-induced apoptosis in cancer cells. AAbs to IL27 and IFNL2 were linked to longer OS, anti-LAG3 to longer PFS, and AAbs to ADRA1A to shorter PFS. LAG3 is an inhibitory checkpoint targeted in cancer therapy to enhance T-cell activation. IL4R supports Th2-skewed, protumor signaling, while IL27 and IFNL2 can promote anti-tumor T-cell responses. Conclusions: We identified baseline AAb profiles associated with clinical outcome in patients treated with mono or combined immune checkpoint blockade (ICB), indicating antigen-specific immune effects that may be either anti- or pro-tumorigenic. These findings highlight a role for B cells and AAbs in melanoma immunotherapy and suggest opportunities to target B cell–related pathways. AAbs to cytokines and receptors, including IL27, IFNL2, ADRA1A, ECE1, TNFRSF10B, TNFRSF1B, and IL4R, support a potential modulatory function in ICB response. Functional validation is needed to clarify their impact on anti-tumor immunity and outcomes.