Since the first reports of clinical success in 2010, PD-1 inhibitors have become standard treatment for a wide number of cancers. However, while for some patients these drugs are a miracle cure, for a frustratingly large minority the therapy has little effect regardless of cancer type.
Kyoto University immunologist Tasuku Honjo, who first identified PD-1, has an unmatched understanding of how PD-1 regulates multi-functional T cells — and why only some patients respond to treatment based on PD-1 inhibition.
“PD-1 regulates autoimmunity. It prevents T cells from attacking host cells. But it also prevents T cells from attacking cancer cells, which are also host cells,” explains Honjo.
In a study published in the Proceedings of the National Academy of Sciences, Honjo and his team of scientists report on a series of molecular events through which PD-1 inhibition could be enhanced to strengthen the anti-cance activity of T cells.
PD-1 blockade therapy has previously been shown to enhance mitochondrial activity in T cells, leading Honjo to theorize that, “the difference between responder and non-responder patients lies in the molecular mechanisms that activate the mitochondria.”
“Mitochondria produce reactive oxygen species (ROS), which are found to enhance PD-1 therapy,” adds first author of the study, Kenji Chamoto.
Chamoto injected FCCP, a chemical that generates ROS, into mice suffering from different types of cancer. Alone, FCCP had no effect on tumor suppression, but combining it with PD-1 inhibitors enhanced any effect compared to its absence.
“Together with PD-1 inhibitors,” says Chamoto, “FCCP increased the functional potency of the T cells by activating mitochondria.”
The team used these findings to uncover which molecules activate mitochondria through ROS. “We found a number of molecules associated with signal cascades for mitochondrial activity. We can target these because they all enhanced the PD-1 blockade effect,” continues Chamoto.
Activation of these mechanisms caused T cells to secrete ‘cytokines’ for the destruction of cancer cells, a status not seen in patients unresponsive to standard PD-1 treatment.
While the discovery of these mechanisms could lead to more effective anticancer therapies in the future, more immediate impact may come from the identification of responders and non-responders.
Explains Honjo, “Cancer patients and doctors do not have time to test different therapies until finding one that works. This research could eventually help identify which patients will respond well to PD-1 inhibitors and which patients need other options.”