Abstract A039: Dynamic change of plasma circulating extracellular vesicles PD-L2 as a predictor of immune response in melanoma patients receiving anti-PD-1 therapy

Abstract Immune checkpoint inhibitors (ICIs) have provided new hope for melanoma patients, however, not all patients benefit. Furthermore, ICI-related therapies cause significant immune-related adverse events that adversely affect patient outcomes. Therefore, there is a pressing need for reliable biomarkers to identify patients most likely to benefit from these treatments. In this study, we employed an extracellular vesicles (EVs) protein expression array to explore the longitudinal membrane protein profiles of plasma-derived EVs from 33 melanoma patients receiving anti-PD-1 and anti-angiogenesis therapy at baseline and early treatment. We found that changes in PD-L2 levels on the EV membrane were associated with patient outcomes. The role of EV PD-L2 as an indication of disease progression and treatment efficacy was validated in an independent cohort of melanoma patients treated with anti-PD-1 monotherapy. Plasma-derived PD-L2+ EVs from patients with mucosal melanoma significantly reduced the frequency of granzyme B+ CD8 T cells within the peripheral blood mononuclear cells (PBMCs) of healthy individuals. The inhibitory effect of PD-L2+ EVs on CD8 T cells was further validated using human melanoma cell lines and the B16-F10 mouse model. Although intratumoral injection of PD-L2+ EVs could promote melanoma growth in vivo, tumors with PD-L2+ EVs showed a higher response to anti-PD-1 than those without PD-L2+ EVs. Collectively, our study demonstrates that PD-L2+ EVs inhibit CD8 T cell activation and promote melanoma growth, and changes in PD-L2 on circulating EVs during early treatment could serve as a biomarker for ICI-based therapy. Citation Format: Jie Dai, Linzi Sun, Xiaoting Wei, Lili Mao, Qian Zhao, Junjie Gu, Caili Li, Jun Guo, Lu Si. Dynamic change of plasma circulating extracellular vesicles PD-L2 as a predictor of immune response in melanoma patients receiving anti-PD-1 therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A039.