A Ludwig Cancer Research study has identified a novel mechanism by which a type of cancer immunotherapy known as CTLA-4 blockade can disable suppressive immune cells to aid the destruction of certain tumors.
The tumors in question are relatively less reliant on burning sugar through a biochemical process known as glycolysis. Researchers led by Taha Merghoub and Jedd Wolchok of the Ludwig Center at Memorial Sloan Kettering Cancer Center (MSK) and former postdoc Roberta Zappasodi--now at Weill Cornell Medicine--have discovered that in a mouse model of glycolysis-deficient tumors, CTLA-4 blockade does much more than stimulate cancer-targeting T cells of the immune system. In such tumors, anti-CTLA-4 therapy also destabilizes and reprograms regulatory T cells (Tregs), which suppress anti-cancer immune responses and often dull the effects of 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 blockade. 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 to improve its efficacy against highly glycolytic tumors by combining it with drugs that inhibit glycolysis."
Jedd Wolchok, Ludwig Center, Memorial Sloan Kettering Cancer Center
Tumors are replete with metabolic adaptations that not only promote their growth, but also serve to cripple the immune cells that attack them. Among these is the tendency of cancer cells to consume large amounts of the sugar glucose through the abnormal employment of glycolysis. This depletes glucose from the tumor's microenvironment, depriving so-called "effector" T cells, like killer T cells, of a nutrient that happens to be essential to their anti-cancer activity.
"The immune cells and cancer cells are competing for glucose, and we wanted to understand that dynamic within the tumor microenvironment in the context of checkpoint blockade immunotherapy," said Wolchok.
This is of interest because, powerful though it is, CTLA-4 blockade often has a limited efficacy, and only against a few types of cancer. Researchers are exploring multiple strategies to boost the effects and broaden the applicability of the therapy, which blocks a protein named CTLA-4 on T cells that serves as an "off switch" to their activation.
Previous studies have shown that simply blocking glycolysis in tumors results in greater infiltration by immune cells. "So, we asked, if glycolysis-deficient tumors are now hot"--or filled with effector T cells--"can we get a better anti-cancer immune response with immune checkpoint blockade," said Merghoub.
To explore the phenomenon, Zappasodi, Merghoub, Wolchok and colleagues generated mouse models implanted with breast tumors deficient in glycolysis. They showed that CTLA-4 blockade and surgery significantly extended the survival of these mice compared to identically treated mice implanted with the unaltered and highly glycolytic tumors. The effect correlated with increased infiltration of T cells into the poorly glycolytic tumors and the establishment of a strong immune memory of the cancer in the mice bearing them.
But what really piqued the interest of the researchers was that the greater infiltration of T cells into the poorly glycolytic tumors extended to Tregs as well, not just the effector T cells that target cancer cells. Analysis of these Tregs showed that they were producing immune factors--interferon-γ and TNF-α--that are normally produced by killer T cells. This did not occur in highly glycolytic tumors.
"When we block CTLA-4, we destabilize the Tregs in glycolysis-deficient tumors," said Zappasodi. "But instead of making the Tregs disappear, the therapy reorients them, so they're not just in a non-suppressive state, but actually switch over to an effector state."
Through a series of sophisticated cell culture experiments, the researchers showed that tumor glycolysis reinforces the functional stability of Tregs to better protect their constituent cancer cells from immune attack. They also charted out the biochemical signaling that functionally destabilizes Tregs in an environment rich in glucose following CTLA-4 blockade.
"Our plan now is to look for drugs that reduce glycolysis within the tumor microenvironment and test their effects on CTLA-4 checkpoint blockade," says Merghoub.
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