VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.
Bottom Line: The recent development of therapies targeting PD-1 and CTLA-4 have raised great interest since they induced long-lasting objective responses in patients suffering from advanced metastatic tumors.However, the regulation of PD-1 expression, and thereby of exhaustion, is unclear.In view of these results, association of anti-angiogenic molecules with immunomodulators of inhibitory checkpoints may be of particular interest in VEGF-A-producing tumors.
Affiliation: INSERM U970, Paris Cardiovascular Research Center, Université Paris-Descartes, Sorbonne Paris Cité, 75015 Paris, France Service d'immunologie biologique, Service d'oncologie médicale, Service de chirurgie digestive, Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, 75015 Paris, France.Show MeSH
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Mentions: To understand whether VEGF-A can act directly on CD8+ T cells, we first analyzed the expression of the two VEGF-A receptors, VEGF-R1 and -R2, on CD8+ T cells in vivo. We observed that these two receptors are expressed only at very low levels in spleens of tumor-free and tumor-bearing mice, but are strongly increased on tumor-infiltrating CD8+ T cells (Fig. 2 a). These VEGFR+ CD8+ T cells also expressed PD-1 (unpublished data). Because tumor-infiltrating T cells bear an activated phenotype unlike splenic CD8+ T cells, these results suggested that VEGFR expression could be associated with T cell activation (Whiteside and Parmiani, 1994). To recapitulate this phenomenon in vitro, we analyzed expression of these receptors after stimulation of purified CD8+ T cells with different doses of anti-CD3 by flow cytometry and confocal microscopy. Expression of VEGF-R1 and -R2 was induced by stimulation with 3 µg/ml of anti-CD3 and became significant at 10 µg/ml after 48 h of culture (Fig. 2, b–d). Because CD8+ T cells can express VEGF receptors after activation, we then analyzed the impact of VEGF-A on these T cells. Anti-CD3 stimulation induced expression of PD-1, but addition of VEGF-A enhanced PD-1 expression on these cells in a dose-dependent manner (Fig. 2, e–f). Furthermore, this effect was blocked when anti–VEGF-A antibody was added to the culture (unpublished data). Thus, VEGF-A directly increases PD-1 expression on activated CD8+ T cells.
Affiliation: INSERM U970, Paris Cardiovascular Research Center, Université Paris-Descartes, Sorbonne Paris Cité, 75015 Paris, France Service d'immunologie biologique, Service d'oncologie médicale, Service de chirurgie digestive, Service d'hépatogastroentérologie et d'oncologie digestive, Hôpital Européen Georges Pompidou, 75015 Paris, France.