VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors

TLDR

Tumor immune escape relies on mechanisms such as T cell exhaustion marked by PD‑1, CTLA‑4, and Tim‑3 expression, and while PD‑1/CTLA‑4 blockade shows clinical benefit, the regulation of PD‑1 remains unclear, with VEGF‑A emerging as a key factor that promotes an immunosuppressive microenvironment. This study demonstrates that tumor‑derived VEGF‑A upregulates PD‑1 and other inhibitory checkpoints on CD8⁺ T cells, and that this effect can be reversed by anti‑angiogenic agents targeting the VEGF‑A–VEGFR axis. Thus, combining anti‑angiogenic therapy with checkpoint inhibitors may enhance antitumor immunity in VEGF‑A‑producing tumors.

Abstract

Immune escape is a prerequisite for tumor development. To avoid the immune system, tumors develop different mechanisms, including T cell exhaustion, which is characterized by expression of immune inhibitory receptors, such as PD-1, CTLA-4, Tim-3, and a progressive loss of function. 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. VEGF-A, a proangiogenic molecule produced by the tumors, plays a key role in the development of an immunosuppressive microenvironment. We report in the present work that VEGF-A produced in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved in CD8+ T cell exhaustion, which could be reverted by anti-angiogenic agents targeting VEGF-A–VEGFR. 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.