The Ludwig Cancer Research study has identified a new mechanism by which a type of cancer immunotherapy called CTLA-4 can block immune cells to help destroy certain tumors. These tumors are largely responsible for burning sugar through a biochemical process called glycolysis.
Researchers are led by Taha Merghoub and Jedd Wolchok from the Ludwig Center at the Sloan Cancer Kettering Cancer (MSK) Memory Center and postdoctoral Roberta Zappasodi-; now at Weill Cornell Medicine-; found that in a mouse model of glycolysis-deficient tumors, CTLA- 4 blokcheyn does much more than stimulate cancer-targeting T cells in the immune system.
In such tumors, anti-CTLA-4 therapy also deregulates and reprogramns regulatory T cells (Tregs), which suppress immune responses against cancer and often reduce side effects. immunotherapies. Their report appears in the current issue of Nature.
“Our study shows that tumors with low levels of glycolysis are more likely to respond to CTLA-4 inhibition,” Wolchok said. “This suggests a new approach to the personalization of anti-CTLA-4 therapy;
Tumors are repelled by metabolic changes that not only stimulate their growth, but also serve the invading immune cells. These include the tendency of cancer cells to consume large amounts of glucose glucose through the use of glycolysis abuse. This releases glucose from the tumor microenvironment, removing “effector” T cells, known as killer T cells, from nutrients essential to their anti-cancer activity.
The immune cells and the cancer cells compete for glucose, and we wanted to understand these dynamics within the microenvironment of the tumor in the context of checkpoint blockade immunotherapy. “
Jedd Wolchok from the Ludwig Center at Sloan Kettering Memory Cancer Center
This is interesting because, while powerful, CTLA-4 inhibition often has limited efficacy, and only against a few types of cancer. Researchers are exploring multiple strategies to strengthen the effect and extend the suitability of the treatment, which blocks a protein called CTLA-4 on T cells that serves as a “turn off” to the activation aca.
Previous studies have shown that direct inhibition of glycolysis in tumors leads to increased infiltration by immune cells. “So we asked, are glycolysis-deficient tumors now hot” -; or filled with effector T cells -; “whether we can get a better immune response against cancer by immune suppression,” Merghoub said.
To study the phenomenon, Zappasodi, Merghoub, Wolchok and colleagues created mouse models implicated in breast tumors that lacked glycolysis. They showed that CTLA-4 inhibition and surgery significantly increased the survival of these mice compared with similarly treated mice inoculated with the unmodified and highly glycolytic tumors. The effect was associated with increased infiltration of T cells into the malignant glycolytic tumors and the establishment of a strong immune memory of the cancer in the mice that carried them.
But what really caught the researchers’ interest was the increased infiltration of T cells into the glycolytic tumors that expanded to Tregs as well, not just the cells T effector targeting cancer cells. A study of these Tregs showed that they produced immune-factors; interferon-γ and TNF-α-; which are usually produced by killer T cells. This did not occur in highly glycolytic tumors.
“When we inhibit CTLA-4, we deregulate the Tregs in glycolysis-deficient tumors,” Zappasodi said. “But instead of forcing the Tregs to disappear, the treatment resets them, so they are not just in a non-suppressive state, but in reality they will turn into a state of influence. . “
Through a series of solitary cell culture experiments, the researchers showed that tumor glycolysis stabilizes the stability of Tregs action to protect their component cancer cells from immune invasion. They would also record out the biochemical markers that actively deactivate Tregs in a glucose-rich environment after CTLA-4 inhibition.
“Our plan now is to look for drugs that reduce glycolysis within the microenvironment of the tumor and test their effect on CTLA-4 blockade,” Merghoub said.