Work

42 Integrated systemic and spatial profiling reveals vascular-immune determinants of response to dual PD-L1 and VEGF blockade in refractory melanoma

Year: 2026

Type: conference-abstract

Abstract: Background Overcoming anti-PD-1 resistance remains a critical need in advanced melanoma. A phase II clinical trial combining PD-L1 blockade with VEGF blockade has demonstrated 40% disease control in refractory patients. However, determinants of immune re-infiltration versus exclusion and resistance remain poorly defined.Methods We leveraged paired, longitudinal peripheral blood samples and tumor biopsies (baseline and on-treatment) from a phase II trial of atezolizumab and bevacizumab in PD-1 refractory metastatic melanoma. Systemic immune and vascular dynamics were decoded using targeted proteomics (Olink) and immunophenotyping (CyTOF), and integrated with spatial tissue profiling via multiplex immunofluorescence (mIF). Longitudinal changes were evaluated using paired non-parametric analyses, comparing patients with disease control (responders) to those with progressive disease (non-responders).Results Responders exhibited functional vascular normalization, evidenced by a significant on-treatment decrease in soluble Tie2 (p = 0.03). This structural remodeling facilitated immune trafficking: responders showed elevated baseline circulating CCL23, followed by a synchronous on-treatment decrease in both CCL23 (p = 0.031) and CD4 + Effector Memory (TEM) cells (p = 0.047). Crucially, spatial mIF profiling validated successful tissue extravasation, revealing a significant on-treatment influx of CD68+ macrophages into the tumor (mirroring the systemic CCL23 gradient) and a simultaneous decrease in intra-tumoral PD-1 expression, consistent with the recruitment of fresh, non-exhausted T-cells. Conversely, non-responders exhibited a vascular sealing phenotype characterized by a significant longitudinal spike in the vascular stabilizer ANGPT1 (p = 0.049). They demonstrated elevated circulating IFN (p = 0.039) and CD4+ TEM cells (p = 0.05) at baseline, followed by a significant accumulation of terminally exhausted CD8+ TEMRA cells (p = 0.0273), suggesting that systemic trapping and continuous peripheral antigen exposure lead to terminal T-cell burnout.Conclusions Clinical benefit from dual PD-L1/VEGF blockade relies on successful systemic and spatial vascular-immune crosstalk. Tie2 reduction and CCL23 chemotaxis facilitate successful immune tumor entry, directly validated by the spatial influx of CD68 + cells and reduction of exhausted PD-1+ populations in the microenvironment. Conversely, compensatory ANGPT1 upregulation creates a non-permissive vascular barrier driving systemic T-cell trapping and terminal CD8+ TEMRA exhaustion, identifying a distinct mechanism of therapeutic failure and offering non-invasive biomarkers for patient stratification. Ongoing integration with paired intra-tumoral multi-omics (scRNA-seq, scTCR-seq) will further validate these systemic dynamics, defining the spatial architecture of this immune exclusion to guide future rational combinations.Ethics Approval The study obtained Ethics Approval through the DF/HCC IRB, protocol # 19-604 and all patients provided informed consent prior to participation in the study.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0042