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TGF-beta signaling impairs T cell-mediated cancer immunity

Reuters Health - 22/10/2020 - Transforming growth factor (TGF)-beta impairs the ability of CD4+ T cells to prevent cancer progression, but blocking TGF-beta signaling in these cells restores their ability to remodel the tumor microenvironment and trigger cancer-cell death, researchers report.

"We were most surprised to find that the immune system can effectively repress cancer progression by targeting the cancer environment rather than the cancer cell itself," Dr. Ming O. Li of Memorial Sloan Kettering Cancer Center and Weill Cornell Graduate School of Medical Sciences, in New York City, told Reuters Health by email.

Blockage of TGF-beta signaling inhibits tumor development, but its functional target and underlying mechanism of cancer regulation remain unclear.

Dr. Li and colleagues investigate the effects of TGF-beta on type-2 immunity to cancer and the impact of targeted TGF-beta-signaling blockade in T helper 2 (Th2) cells on the tumor microenvironment and cancer progression in two separate studies described in Nature.

In the first study, the team shows that TGF-beta signaling represses Th2-cell responses that reprogram tumor vasculature and suppress cancer progression.

Depletion of TGF-beta receptor 2 (TGFBR2) in CD4+ T cells halts cancer progression as a result of tissue healing and remodeling of the blood vasculature, which together cause cancer-cell hypoxia and death in distant avascular regions.

Similar effects are not seen after depletion of TGFBR2 in CD8+ T cells.

The overall protective response depends on the Th2 cytokine interleukin-4, but not on the Th1 cytokine interferon-gamma, suggesting that this type-2 immunity plays a prominent role in restraining angiogenesis and tumor progression in subsets of patients with cancer.

In the second study, the researchers show that blocking TGF-beta signaling in CD4+ T cells remodels the tumor microenvironment and restrains cancer progression.

Genetic deletion of TGFBR2 in CD4+ T cells in a mouse model of breast cancer suppressed tumor growth, as did pharmacological blockade with a non-immunosuppressive antibody (CD4 TGF-beta Trap, or 4T-Trap).

4T-Trap treatment selectively inhibited Th-cell TGF-beta signaling in tumor-draining lymph nodes, causing IL-4-dependent reorganization of tumor vasculature and cancer-cell death.

4T-Trap-induced tumor-tissue hypoxia led to increased VEGFA expression, but VEGF inhibition enhanced the effects of 4T-Trap.

"We know that the immune system is incredibly adept at recognizing harmful invaders and attacking them with precision," Dr. Li said. "However, that is not the only way our immune system protects us from threats; it also promotes healing of damaged tissue so that pathogens cannot take root in the body. We now show that this latter role can also be enlisted in the fight against cancer."

"4T-Trap can be combined with U.S. Food and Drug Administration-approved antiangiogenics drugs such as VEGF-Trap to further restrain tumor-vasculature-mediated cancer progression," he said. "This new cancer-environment-focused immune-based approach (cancer-environment immunotherapy) may help patients that do not respond to other therapies."

"Helper T cells can be considered the immune system's 'Commanders-in-Chief,' because they direct the class and magnitude of immune responses," Dr. Li said. "Future research focusing on their regulatory functions in tumors may lead to novel cancer immunotherapy targets and strategies."

By Will Boggs MD

SOURCE: https://bit.ly/3dPn7ZR and https://bit.ly/35rVAto Nature, online October 21, 2020.

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