Co-targeting of VEGFR2 and PD-L1 promotes survival and vasculature normalization in pleural mesothelioma

Our plain-English summary of Co-targeting of VEGFR2 and PD-L1 promotes survival and vasculature normalization in pleural mesothelioma, by S. Rovers, J. Van Audenaerde, R. Verloy, et al (Oncoimmunology, 2025).

The study

• Authors: S. Rovers, J. Van Audenaerde, R. Verloy, J. De Waele, L. Brants, C. Hermans, H.W. Lau, C. Merlin, M. Möller Ribas, P. Ponsaerts, S. Van Laere, F. Lardon, A. Wouters, S.A. Fisher, J. van Meerbeeck, E. Marcq, E. Smits
• Journal: Oncoimmunology
• Published: 2025;14(1):2512104
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is an aggressive cancer caused by asbestos exposure, with limited treatment options and poor prognosis, highlighting the need for more effective therapies. Combining immune checkpoint blockade with anti-angiogenic therapy has shown potential in other cancers. Our study investigated the combined inhibition of PD-L1 and VEGFR2 in a mouse model of PM. Using C57BL/6 mice with subcutaneous AE17 mesothelioma tumors, we assessed the effects of anti-PD-L1 therapy with induction, concomitant, or consolidation anti-VEGFR2 treatment. Mice received intraperitoneal doses every three days for three treatments. Tumor growth, survival, tumor-infiltrating immune cells and intra-tumoral vasculature were analyzed. Results demonstrated that combining anti-PD-L1 with induction or concomitant anti-VEGFR2 significantly delayed tumor growth, improved survival, and promoted vascular maturation. Flow cytometry suggested T cell exhaustion in monotherapy groups, while no significant changes were seen with concomitant treatment. Depleting CD4+ T cells reversed the positive effects of concomitant treatment. These findings suggest that dual inhibition of PD-L1 and VEGFR2 is a promising therapeutic approach for PM, with CD4+ T cells playing a critical role in the immune response. This dual targeting of immune checkpoints and angiogenesis offers a potential new avenue for improving outcomes in PM treatment and warrants further clinical exploration.

In plain English

This was a laboratory study in mice, supported by an analysis of public data on 87 patients with pleural mesothelioma. It tested drug treatments and did not study asbestos exposure. Mouse mesothelioma cells (the AE17 line) were injected under the skin of female mice. The mice then received an antibody blocking PD-L1, an antibody blocking VEGFR2 (a receptor involved in blood-vessel growth), or both. When both were used, VEGFR2 blockade was given before, together with, or after PD-L1 blockade. In the patient data, high VEGFR2 protein levels were linked with worse progression-free and disease-specific survival. In mice, giving VEGFR2 blockade before or together with PD-L1 blockade improved survival compared with PD-L1 blockade alone or the 'after' schedule. Tumors under these two schedules showed signs of more mature blood vessels. Removing CD4+ T cells, a type of immune cell, reversed the combination's control of tumor growth. The authors concluded that blocking both targets is a promising approach for pleural mesothelioma. They noted that the tumors grew under the skin rather than in the lining of the chest.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (mouse tumor model), with a supporting analysis of public patient gene and protein data from The Cancer Genome Atlas (TCGA)
• Who was studied: 319 female C57BL/6J mice (6 to 8 weeks old) at the University of Antwerp, Belgium, injected under the skin of the flank with AE17 mouse epithelioid mesothelioma cells. A separate analysis used TCGA data from 87 patients with pleural mesothelioma.
• Exposure: No asbestos exposure was studied. Mice received an anti-PD-L1 antibody (clone 10F.9G2, 200 µg) and/or an anti-VEGFR2 antibody (clone DC101, 800 µg chosen after testing 100 to 800 µg). Doses were given by injection into the abdomen once every 3 days for 3 doses. In combination groups, anti-VEGFR2 was given as induction (before), concomitant (with) or consolidation (after) treatment.
• Main results:
  • In the 87 TCGA pleural mesothelioma patients, high VEGFR2 protein expression was associated with worse progression-free survival (HR = 1.647, p = 0.013) and disease-specific survival (HR = 1.44, p = 0.004). No association with overall survival was found (p = 0.117).
  • In mice given anti-VEGFR2 alone, survival improved compared with untreated controls at 400 µg and 800 µg, but not at 100 µg or 200 µg. The 800 µg dose was selected for later experiments.
  • Mice given concomitant treatment had a longer delay in tumor growth than mice given anti-PD-L1 alone (p < 0.001) and mice given the consolidation schedule (p = 0.009).
  • Survival was better in mice given the induction or concomitant combination than in mice given anti-PD-L1 alone (p = 0.0001 and p = 0.0018, respectively). It was also better than in mice given the consolidation regimen (p = 0.0012 and p = 0.0064, respectively).
  • Compared with anti-VEGFR2 alone, the survival advantage of the concomitant (p = 0.09) and induction (p = 0.08) combinations was a trend that was not statistically significant.
  • Tumors from the induction and concomitant groups showed traits suggestive of a more mature blood-vessel network. The concomitant group showed 4 of the 6 characteristics evaluated. The anti-VEGFR2 alone and consolidation groups showed no signs of vessel normalization.
  • No significant changes were found in the hypoxia (low-oxygen) marker CA9.
  • PD-1 expression on CD8+ T cells was increased in both single-drug groups and in the consolidation group. The authors said this could suggest T cell exhaustion.
  • In mice given concomitant treatment, removing CD8+ T cells did not significantly change tumor growth (p = 0.971) or survival (p = 0.0964).
  • In mice given concomitant treatment, removing CD4+ T cells reversed the effect of the combination, with significant loss of tumor growth control (p < 0.001). The tumors also had fewer CD31+ endothelial (blood-vessel lining) cells and a sparse vessel network.
  • Removing CD25+ regulatory T cells improved tumor growth control compared with concomitant treatment alone (p = 0.023). Survival differences for CD4 removal (p = 0.0823) and CD25 removal (p = 0.0727) followed the same pattern but were not statistically significant.
• The authors' conclusion: The authors concluded that blocking both PD-L1 and VEGFR2 is a promising therapeutic approach for pleural mesothelioma, with CD4+ T cells playing a critical role in the immune response.
• Limitations the authors state:
  • The tumors were grown under the skin (subcutaneous model) rather than in the pleura, where pleural mesothelioma occurs. The authors said studies in orthotopic models are needed.
  • Immune cell numbers in the tumors were low. The authors said statistically significant differences reflected small absolute changes rather than a substantial biological effect.
  • Hypoxia was not measured at earlier time points after treatment, when a reduction might have occurred.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Mesothelioma, Asbestos Exposure, Prognosis, Mesothelioma, Consolidation, Angiogenesis.

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