Deep immune profiling of stage III resected melanoma patients undergoing anti-PD1 adjuvant therapy unveils critical immunophenotypes associated with tumor recurrence or adverse effects

Introduction Immune checkpoint blockers (ICB) are standard of care as adjuvant therapy for patients with resected high-risk melanoma, yet many patients suffer from immune-related adverse effects (AEs), while others experienced tumor relapse. Identification of biomarkers capable of predicting tumor relapse or understanding the occurrence of AEs remains a major challenge to improve outcomes and develop efficient and more tolerated strategies. Methods We explored the immune landscape at baseline and during treatment in blood of resected stage III melanoma patients treated with anti-PD-1 adjuvant therapy and evaluated its association with tumor recurrence and occurrence of AEs. Through a comprehensive immunomonitoring based on multi-parametric flow cytometry combined with multiplex immunoassays, we depicted DC, monocyte, and effector subsets and examined their detailed phenotypic and functional features together with soluble factors in plasma. Immune features were compared between groups using both supervised and unsupervised computational machine-learning analyses. Results We revealed distinct immune landscape between non-relapsing (NP) and progressive (PD) melanoma patients as well as immune profiles associated with occurrence of AEs, with modulated innate and adaptive immunophenotypes together with functional perturbations. We highlighted innovative predictive signatures associated with clinical outcome: plasmatic ULBP3/4 and CD73 levels, importance of DC3 and monocyte subsets, relevance of new checkpoints (Gal9/TIM3 and CD155/TIGIT). Discussion We uncovered candidate immunophenotypes associated with tumor recurrence or AEs in stage III melanoma patients treated by anti-PD1 adjuvant therapy. Deciphering such challenges is promising to optimize ICB efficacy while reducing AEs, and design pertinent combination strategies to achieve better clinical successes in future.