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How immunometabolic editing drives immune evasion and tumor evolution

Ping-Chih Ho, Ludwig Cancer Research Lausanna
Ping-Chih Ho

A study led by Ludwig Lausanne’s Ping-Chih Ho discovered that the immune system’s surveillance of cancer can itself induce metabolic adaptations in the cells of early-stage tumors that simultaneously promote their growth and equip them to suppress lethal immune responses. Published in a January issue of Cell Metabolism, the study detailed the precise mechanism by which this “immunometabolic editing” of emergent tumors occurs in mouse models of the skin cancer melanoma. Ping-Chih and his team found that three proteins—IFNγ, STAT3 and c-Myc—orchestrate the process. Secreted by immune cells, IFNγ blocks the growth of tumors. But its signaling via STAT1 also helps cancer cells adapt to evade T cell attack—a process known as immunoediting. The researchers found that IFNγ additionally activates a signaling pathway mediated by STAT3 that induces epigenetic changes and hyperactivates the master regulator of cell metabolism c-Myc, which is often aberrantly active in cancer. Several genes activated by c-Myc, they found, also compromise T cell function and infiltration into tumors. STAT1 and STAT3 signaling pathways, in fact, synergize to confer on emergent tumors the ability to evade immune responses, driving the immunometabolic editing that enables full-blown malignancy. The findings suggest STAT3 as well as 40 metabolic c-Myc-regulated genes involved in immunometabolic editing whose products could be prime targets for cancer therapy.

Immunoediting instructs tumor metabolic reprogramming to support immune evasion
Cell Metabolism, 2023 January 3

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