Researchers report that the immune system's cancer-killing T cells are more effective in a tumor's anoxic environment when they have access to vascular endothelial growth factor A (VEGF-A). In a study (“An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression”) from the Karolinska Institutet published in Cancer Cell, the scientists show how the T cells not only survive in this oxygen-depleted microenvironment with the help of hypoxia-inducible transcription factor-1α (HIF-1α) but also become more effective at killing cancer cells inside it.
“Cytotoxic T cells [important for the immune system in their ability to kill tumor cells] infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization,” write the investigators.
“Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity.”
“We observed that the T cells detect oxygen, and by adapting to a limited amount of oxygen they can enter anoxic tumors, survive within them, and then effectively kill them,” says Randall Johnson, Ph.D., in the department of cell and molecular biology, who led the study.
The researchers also used mouse models to try to knock out VEGF-A (a growth factor that makes blood vessels grow and one of HIF's target genes) from their T cells.
“Doing this, we found that the tumors grew and that the formation of new blood vessels changed,” explains Dr. Johnson. “This is interesting because it was previously thought that tumors starve when you reduce VEGF-A. Our research shows that things are more complex than this. I hope that our discovery will lead to better tumor therapy that maximizes the effect of the T cells.”