TGF-β suppresses type 2 immunity to cancer

The immune system uses two distinct defence strategies against infections: microbe-directed pathogen destruction characterized by type 1 immunity(1), and host-directed pathogen containment exemplified by type 2 immunity in induction of tissue repair(2). Similar to infectious diseases, cancer progresses with self-propagating cancer cells inflicting host-tissue damage. The immunological mechanisms of cancer cell destruction are well defined(3-5), but whether immune-mediated cancer cell containment can be induced remains poorly understood. Here we show that depletion of transforming growth factor-beta receptor 2 (TGFBR2) in CD4(+)T cells, but not CD8(+)T cells, halts cancer progression as a result of tissue healing and remodelling of the blood vasculature, causing cancer cell hypoxia and death in distant avascular regions. Notably, the host-directed protective response is dependent on the T helper 2 cytokine interleukin-4 (IL-4), but not the T helper 1 cytokine interferon-gamma (IFN-gamma). Thus, type 2 immunity can be mobilized as an effective tissue-level defence mechanism against cancer. Depletion of transforming growth factor-beta receptor 2 (TGFBR2) in CD4(+)T cells results in IL-4-dependent vascular remodelling, stopping tumour growth in a transgenic mouse model of breast cancer, suggesting that type 2 immunity could be targeted for cancer treatments.