Figure 2 from Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti–PD-1 and Anti–PD-L1 Treatment in a Checkpoint Refractory Melanoma Model

https://doi.org/10.1158/2326-6066.30721186

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posted on 2025-11-26, 12:46 authored by Rosanne E. Veerman, Gözde Güclüler Akpinar, Annemarijn Offens, Loïc Steiner, Pia Larssen, Andreas Lundqvist, Mikael C.I. Karlsson, Susanne Gabrielsson

Combination treatment of EVs and anti–PD-1/anti–PD-L1 improves antitumor immunity on day 20 after tumor inoculation. A, Mice with OVA-expressing B16 melanoma were treated with PBS or EVs intravenously and anti–PD-1/PD-L1 intraperitoneally as indicated. Mice were sacrificed on day 20 for further analysis. B, Tumor volume was measured on day 20. C, The total number of OVA-specific CD8+ T cells in the spleen was determined using flow cytometry. D, ELISPOT assay was performed to detect IFNγ-secreting cells after in vitro restimulation with the CD4 peptide OVA323–339, CD8 peptide SIINFEKL, whole OVA protein, or B16 melanoma cells. The data represent one experiment. Dots represent a single mouse, 4 to 5 mice per group, and data are presented as the mean ± SEM, except for figure 2C which is displayed as the mean ± SD. Data were analyzed using the Kruskal–Wallis test with Dunn test for multiple comparisons. *, P < 0.05; **, P < 0.01; and ***, P < 0.001.

Funding

Vetenskapsrådet (VR)

Cancerfonden (Swedish Cancer Society)

Radiumhemmets Forskningsfonder (Cancer Research Foundations of Radiumhemmet)

Stockholm läns landsting (Stockholm County Council)

Hjärt-Lungfonden (Swedish Heart-Lung Foundation)

Karolinska Institutet (KI)

History

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DOI - Is supplement to Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti–PD-1 and Anti–PD-L1 Treatment in a Checkpoint Refractory Melanoma Model

ARTICLE ABSTRACT

Extracellular vesicles (EV) are important mediators of intercellular communication and are potential candidates for cancer immunotherapy. Immune checkpoint blockade, specifically targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, mitigates T-cell exhaustion, but is only effective in a subset of patients with cancer. Reasons for therapy resistance include low primary T-cell activation to cancer antigens, poor antigen presentation, and reduced T-cell infiltration into the tumor. Therefore, combination strategies have been extensively explored. Here, we investigated whether EV therapy could induce susceptibility to anti–PD-1 or anti–PD-L1 therapy in a checkpoint-refractory B16 melanoma model. Injection of dendritic cell–derived EVs, but not checkpoint blockade, induced a potent antigen-specific T-cell response and reduced tumor growth in tumor-bearing mice. Combination therapy of EVs and anti–PD-1 or anti–PD-L1 potentiated immune responses to ovalbumin- and α-galactosylceramide–loaded EVs in the therapeutic model. Moreover, combination therapy resulted in increased survival in a prophylactic tumor model. This demonstrates that EVs can induce potent antitumor immune responses in checkpoint refractory cancer and induce anti–PD-1 or anti–PD-L1 responses in a previously nonresponsive tumor model.