Transforming Growth Factor-b Suppresses Type 2 Immunity to Cancer

The immune system employs two distinct defense strategies against infections: pathogen elimination typified by type 1 immunity, and pathogen containment exemplified by type 2 immunity concomitant with tissue repair. Akin to infectious diseases, cancer progresses with cancer cell acquisition of microorganism-like behavior propagating at the expense of the host. While immunological mechanisms of cancer cell elimination are well defined, whether immune-mediated cancer cell containment can be induced is poorly understood. Here we show that ablation of transforming growth factor-β receptor II (TGFβRII) in CD4+ T cells promotes tumor tissue healing and halts cancer progression. The restorative response is associated with remodeling of the blood vasculature patterning with cancer cell hypoxia and death instigated in avascular regions, a process dependent on the T helper 2 cytokine IL-4. Thus, type 2 immunity represents an effective cancer defense mechanism, and TGFβ signaling in helper T cells may be targeted for tissue-level cancer immunotherapy. Tumor-infiltrating CD4+CD25- T cells were collected from 23-week-old Tgfbr2fl/flPyMT (wild-type, WT; n=2 replicates), ThPOKCreTgfbr2fl/flPyMT (knockout, KO; n=2 replicates with 2 technical repeats, i.e., independent library prepared from the same RNA extraction), Il4-/-Tgfbr2fl/flPyMT (Il4-/-; n=2 replicates) and Il4-/-ThPOKCreTgfbr2fl/flPyMT (Il4-/-KO; n=2 replicates) mice.