Ludwig Cancer Research research reveals metabolic vulnerabilities

February 15, 2021 New York – A study by Ludwig Cancer Research reveals a new mechanism by which a type of cancer immunotherapy known as CTLA-4 blockade can neutralize suppressive immune cells and help destroy specific tumors it was done. The tumor in question is relatively less dependent on the burning of sugar by a biochemical process known as glycolysis.

Researchers led by Tahamelgoub and Jedwolchok of the Ludwig Center at the Memorial Sloan-Kettering Cancer Center (MSK) and former postdoctoral Robert Zappa Sodi (now Weil Cornell Medicine) have blocked CTLA-4 in a mouse model of glycolytic deficient tumors. We have found that it does more than stimulate T cells that target cancer of the immune system. In such tumors, anti-CTLA-4 therapy destabilizes and reprograms regulatory T cells (Tregs). This often suppresses the anticancer immune response and makes immunotherapy less effective. Their report appears in the latest issue of Nature.

“Our study shows that tumors with low levels of glycolysis are more likely to respond to CTLA-4 blockade,” said Wolchok. “It treats patients with these types of tumors with more selective use of anti-CTLA-4 therapy and improves their effectiveness against glycolytic tumors when combined with drugs that inhibit glycolysis. It suggests a new way. “

Tumors are full of metabolic adaptations that not only promote their growth, but also help deprive the immune cells that attack them. Among these, cancer cells tend to consume large amounts of glucose glucose through the abnormal use of glycolysis. This depletes glucose from the tumor’s microenvironment and happens to deprive so-called “effector” T cells, such as killer T cells, of nutrients essential for anticancer activity.

“Immune cells and cancer cells are competing for glucose. We wanted to understand its dynamic changes within the tumor microenvironment in the context of checkpoint-blocking immunotherapy,” said Wolchok. ..

This is interesting. This is because CTLA-4 blockade is strong, but often has limited efficacy and is only for a small number of types of cancer. Researchers are exploring multiple strategies to increase efficacy and extend treatment coverage. It blocks proteins named CTLA-4 on T cells and acts as an “off switch” to their activation.

Previous studies have shown that simply blocking tumor glycolysis increases immune cell infiltration. We asked if “so the glycolytically deficient tumor is now hot” or if it is filled with effector T cells. “Can immune checkpoint inhibition provide a better anti-cancer immune response,” says Merghoub.

To investigate this phenomenon, Zappasodi, Merghoub, Wolchok and colleagues created a mouse model transplanted with a breast tumor that lacks glycolysis. They showed that CTLA-4 blockade and surgery significantly prolonged survival in these mice compared to the same treated mice transplanted with unchanged hyperglycolytic tumors. .. This effect correlated with increased T cell infiltration into tumors with low glycolysis and the establishment of strong immune memory of cancer in mice with them.

However, what was intriguing to the researchers was that the greater infiltration of T cells into tumors with low glycolysis spread to Tregs as well as effector T cells that target cancer cells. Analysis of these Tregs showed that they produced the immune factors (interferon-γ and TNF-α) normally produced by killer T cells. This did not occur in tumors with high glycolysis.

“Blocking CTLA-4 destabilizes regulatory T cells in glycolytically deficient tumors,” says Zappasodi. “But instead of eliminating the Tregs, the treatment turns them around, so the Tregs are not only in an unsuppressed state, they actually switch to an effector state.”

Through a series of sophisticated cell culture experiments, researchers have shown that tumor desalination enhances the functional stability of regulatory T cells and better protects the constituent cancer cells from immune attack. .. They also demonstrated biochemical signaling that functionally destabilizes Tregs in a glucose-rich environment after CTLA-4 blockade.

“Our current plan is to look for drugs that reduce glycolysis in the tumor microenvironment and test their effect on CTLA-4 checkpoint blockade,” says Melghoub.

This study was supported by Ludwig Cancer Research, Swim Across America, Parker Institute for Cancer Immunotherapy, US National Cancer Institute, Breast Cancer Research Foundation, Swiss National Science Foundation, and European Research Council.

Taha Merghoub is a co-director of the Ludwig Collaborative & Swim Across America Institute at MSK and a professor of immunology research in medicine at Weill Cornell Medical College.

Jedd Wolchok is a co-director of the Ludwig Center and Ludwig Collaborative & Swim Across America Institute and is responsible for MSK’s Immuno-Oncology Services, Human Oncology and Cause Program.

Roberta Zappasodi is an assistant professor at Weill Cornell Medicine.