Novel Anti-PD1 Predictive Signature and Functional Dendritic-Cell Biomarkers in Melanoma Identified with Systems Immunology

Despite the success of anti-PD1 immunotherapy in melanoma, identifying biomarkers for response prediction and rational treatment combinations remains a major challenge. Effective dendritic cell (DC):CD8+ T cell crosstalk in the tumor microenvironment enhances anti-PD1 responses; however, no predictive signatures reflect this interaction. To address this, we developed a systems immunology approach based on DC:CD8+ T cell crosstalk reference biomarkers CD74 and CD8A, leading to the discovery of a 15-gene immune signature called PRIME, incorporated into a logistic regression framework for anti-PD1 response prediction in melanoma. PRIME outperforms previous signatures, especially in tumors with high CD8+ T cells, reflecting a functional immune response. Integrating clinical, molecular, spatial, and single-cell profiling identified SLAMF7 and TYMP as new functional biomarker candidates in DCs. Mechanistic studies revealed that these biomarkers regulate antigen processing and presentation in DCs. Our study demonstrates a new strategy for predicting anti-PD1 responses in melanoma, revealing biomarkers with functional roles that may inform future therapeutic development.