Newswise – JANUARY 05, 2023, NEW YORK – A Ludwig Cancer Research study found that cancer surveillance by the immune system may itself induce metabolic adaptations in early-stage tumor cells that simultaneously promote their growth and equip them to suppress lethal immune responses.
Led by Ludwig Lausanne Associate Member Ping-Chih Ho and published in cellular metabolism, the study details the precise mechanism by which this ‘immunometabolic editing’ of emerging tumors occurs in mouse models of skin cancer melanoma and identifies a novel cascade of biochemical signals and proteins that orchestrate its effects. In addition to illuminating a previously unknown dimension of tumor evolution, the findings hold great promise for improving the efficacy of cancer immunotherapy.
“We have discovered dozens of metabolic enzymes that contribute to immune evasion in melanoma tumors,” said Ho. “These enzymes, as well as some of the individual signaling pathway components that we identified, represent a rich treasure trove of potential drug targets for undermining the defenses erected by immunometabolic editing. Such drugs could make tumors vulnerable to immune clearance and could also be used in combination with checkpoint blockade and other immunotherapies to overcome the resistance most tumors have to such treatments.
The immune system’s surveillance of tumors is thought to contribute to malignancy by driving the evolution of tumor cells which can undermine the mechanism of immune detection and attack. This theory of “immunoediting”—most notably developed by former Chief Science Officer and CEO of the Ludwig Institute for Cancer Research, the late Lloyd Old, and current Ludwig Science Advisory Board member Robert Schreiber—is now a core tenet of the tumor immunology.
Researchers have also long known that metabolic adaptations common to cancer cells, such as their greedy consumption of the sugar glucose, undermine anti-tumor immune responses. What was not clear, however, was whether immune surveillance could also induce metabolic adaptations in cancer cells and whether such adaptations could also help them resist immune responses. This is what the current study has established, exposing an aspect of tumor evolution that has been hypothesized but has so far not been proven.
Ho and his colleagues identify three key proteins that orchestrate this effect: IFNγ, STAT3 and c-Myc. A tool of anticancer surveillance, IFNγ is secreted by T cells and other immune cells and is known to block the growth of cancer cells. But the signaling it triggers, mediated by a protein called STAT1, also induces adaptations in cancer cells that help them evade attack by T cells, the process known as immunoediting.
The researchers show in the present study that IFNγ also activates a distinct and poorly explored signaling pathway mediated by a related protein called STAT3. This pathway alters the expression patterns of the cancer cell genome by inducing ‘epigenetic’ changes that determine which genes are active. It also overactivates a master regulator of cellular metabolism known as c-Myc, which is overexpressed in many types of cancer.
The researchers show that c-Myc-activated genes not only shape cancer metabolism, but also impair T-cell infiltration into tumors and disable their attack on tumor cells. Indeed, STAT1- and STAT3-mediated signaling pathways appear to synergize to give emerging tumors the critical ability to avoid immune clearance, driving immunometabolic editing that helps enhance their evolution into full-blown malignancy.
“Previous studies have shown that loss of STAT3 activity in cancer cells promotes immune infiltration and induces tumor regression,” Ho said. “Our results here explain why and suggest that targeting STAT3 with a drug could restore IFNγ sensitivity in cancer cells that have evolved beyond its inhibitory range.”
The researchers also used CRISPR genome editing to examine 2,078 metabolic enzymes in mouse tumors and identified 40 c-Myc-controlled metabolic genes that play an important role in helping cancer cells evade immune surveillance and attack. These enzymes are also prime candidates for drug targeting.
“Aside from its pharmacological implications,” says Ho, “this study exposes a previously unappreciated dimension of immunoediting that will affect our understanding of the metabolic crosstalk between tumor cells and immune cells in the tumor microenvironment.”
In addition to Ludwig’s position, Ping-Chih Ho is an associate professor at the University of Lausanne.
This study was supported by Ludwig Cancer Research, the European Research Council, the Swiss National Science Foundation, the Institute for Cancer Research, the Melanoma Research Alliance, the European Molecular Biology Organization, the Taiwan Ministry of Science and Technology, the National Defense Medical Center, Agricultural Biotechnology Research Center and Sinica Academy, North Carolina State University, Damon Runyon Cancer Research Foundation, METAvivor, American Association for Cancer Research, Incyte, US National Institutes of Health and Salk Institute for Biological Sciences.
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About Ludwig’s cancer research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists who have pioneered cancer research and major breakthroughs for more than 50 years. Ludwig combines basic science with the ability to translate his findings and conduct clinical trials to accelerate the development of new cancer diagnoses and therapies. Since 1971, Ludwig has invested nearly $3 billion in life-changing science through the non-profit Ludwig Institute for Cancer Research and the six US-based Ludwig Centers. For more information, visit www.ludwigcancerresearch.org.