Cells of the tumor microenvironment compensate for the loss of Tregs
The depletion of regulatory T cells from tumors has been shown in multiple studies using mouse models to suppress cancer growth, though most tumors progress following a brief hiatus. One possible explanation for this is that the loss of Treg cells—which not only prevent runaway immune responses but also participate in wound repair—induces compensatory responses in other noncancerous cells of the tumor microenvironment (TME). Examining this possibility, researchers co-led by Ludwig MSK Director Alexander Rudensky discovered that Tregs influence the gene expression programs of other cells, such as fibroblasts, macrophages and endothelial cells that line blood vessels, in the lung tumor TME and in tissue inflamed by injury. They reported in a May paper in Nature Immunology that these effects are largely conserved in human lung tumors and showed how they might be exploited for the identification of potential combination immunotherapies. In a mouse model of lung cancer that replicates human cancers that are unresponsive to PD-1 checkpoint blockade, Treg depletion activated compensatory responses involving the upregulation of VEGF and CCR2 signaling-related genes. Alexander and his colleagues demonstrated that selectively depleting intratumoral Tregs while targeting VEGF overcomes the tumor’s resistance to PD-1 blockade and significantly extends survival of the mice.