Studies suggest new ways to personalize anti-CTLA-4 therapy for cancer

A study by Ludwig Cancer Research has identified a new mechanism by which a type of cancer immunotherapy known as CTLA-4 blockade can nullify suppressive immune cells to help destroy certain tumors. The tumor in question is relatively less dependent on the burning of sugar by a biochemical process known as glycolysis.

Researchers led by Taha Melgoub and Jed Walchok of the Ludwig Center at the Memorial Sloan-Kettering Cancer Center (MSK) and former postdoc Roberta Zappasodi (now Weil Cornell Medicine) have found that glycolytic deficient tumors. I found CTLA- in a mouse model. 4 Blockade does more than just stimulate cancer targets. T cells 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. “This suggests a new way to personalize anti-CTLA-4 therapy-; by using it more selectively to treat patients with these types of tumors-; and its improvement. Effectiveness For tumors with high glycolysis by combining with drugs that inhibit glycolysis. “

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 compete for glucose, and I wanted to understand its dynamics within the tumor microenvironment in the context of checkpoint-blocking immunotherapy. “

Jedwolchok at the Ludwig Center at the Memorial Sloan Kettering Cancer Center

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. “So, is the glycolytic deficient tumor hot now?”-; Or is it filled with effector T cells-; “Can immune checkpoint inhibition provide a better anti-cancer immune response?” Merghoub said.

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- ;. These are usually 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.