Cancer immunotherapy--an approach that removes the barriers that protect cancer cells from a patient's immune system--has revolutionized the treatment of many cancer types. About 40 percent of melanoma patients, for example, respond to immunotherapy, enabling the immune system's T cells to attack cancer cells and take control of the disease.
In a study published in the the journal Nature, an international team demonstrates, in mice, that they can boost the tumor control rate from around 40 percent up to nearly 100 percent by opening up a parallel pathway.
This study, "Anti-tumor immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells," relies on manipulating these cells, which are a crucial component of the immune system. The primary function of dendritic cells is to process antigens and present them to T cells. They act as messengers, connecting the innate and the adaptive immune systems.
But a protein known as YTHDF1 influences antigen processing by dendritic cells. YTHDF1 controls the level of proteases that destroy potential tumor antigens. This limits their presentation to T cells.
These limits were a problem. But when the researchers eliminated YTHDF1, the dendritic cells increased their ability to engulf peptides, degrade them and present them to T cells. This opened up a new and potentially effective approach to treatment of cancer in patients who do not respond well to checkpoint inhibitors.
"Once we combined YTHDF1 knock-out with the checkpoint inhibitor anti PD-L1, we got almost complete tumor control in a mouse model," the author said. Instead of a 40 percent response, nearly 100 percent of treated mice with melanoma responded to anti-PD-L1.
The researchers confirmed that dendritic cells from mice that lacked YTHDF1 were more effective at antigen-presentation than dendritic cells from normal, wild-type mice. "Our data show that loss of YTHDF1 in dendritic cells attenuates antigen degradation and leads to improved cross-presentation and better cross-priming of CD8+ T cells," according to co- corresponding author.
Together the team performed an additional test using biopsies from human patients with colon cancer, a disease that is much less responsive to immunotherapy than melanoma. They found that tissue from patients with high levels of YTHDF1 had limited T cell infiltration, but patients with low levels of YTHDF1 had more T cell infiltrates. "This suggests that humans correlate nicely with our mouse data," the author added.
This supports the notion that reduced YTHDF1 often coincides with the T cell inflamed tumor microenvironment, which is crucial for successful immunotherapy, the authors note. YTHDF1 could be a therapeutic target for immunotherapy in combination with emerging checkpoint inhibitors or dendritic cell vaccines.
"It will be really interesting to test how the human system works with potential dendritic cell vaccines or small molecule inhibitors that can suppress the activity of YTHDF1 in human cancer patients," according to corresponding author.
Dendritic cell manipulation to achieve total tumor regression
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