The protein YTHDF1 enhances the anti-tumor response

One reason that cancer cells can thrive is that they are able to escape from your immune system. Immunotherapy is a type of biological therapy that helps your immune system fight cancer. The immune system plays an important role in battling infections and other diseases. 

Recently, a study conducted by a University of Chicago-based team together with scientists at Tsinghua University and the Chinese Academy of Sciences has reported that they can increase the tumor control rate from about 40 percent up to almost 100 percent in mice by developing a parallel pathway. Their findings were published in Nature on February 6, 2019.

The dendritic cells are mainly responsible for processing antigens and presenting them to T cells. They act as messengers, linking the innate and adaptive immune systems.

However, a protein called YTHDF1 affects antigen processing in dendritic cells. The protein was discovered and identified in 2015. YTHDF1 controls protease levels that damage potential tumor antigens. This limits their presentation to T cells.

But when the researchers knocked out YTHDF1, the dendritic cells increased their ability to phagocytose peptides, degrade them and present them to the T cells. This opens up a new and potentially effective treatment for cancer in patients who do not respond well to checkpoint inhibitors.

The team combined the YTHDF1 gene knockout with the checkpoint inhibitor anti-PD-L1 and found that almost 100 percent of mice treated with melanoma responded to PD-L1 rather than 40 percent. This means that they have almost complete tumor control in the mouse model.

The researchers confirmed that dendritic cells in YTHDF1-deficient mice were more effective at antigen presentation than dendritic cells in normal wild-type mice. Their data suggested that deletion of YTHDF1 in dendritic cells attenuates antigen degradation and improves CD8 + T cell cross-presentation and better cross-initiation.

And then, the research team used biopsies from colon cancer patients for additional tests that showed a much lower response to immunotherapy than melanoma. They found that T cell infiltration was limited in patients with high YTHDF1 levels, but increased in patients with low YTHDF1 levels. This indicated that humans are well correlated with the mouse data.

An important question in cancer treatment is how we can get better antigen presentation. This study gives the immune system a whole new set of targets, from new antigen sets to potential anti-cancer vaccines. It's an interdepartmental, interdisciplinary collaboration that can lead to unexpected discoveries.

The authors noted that this supported the idea that reducing the overlap of YTHDF1 with the tumor microenvironment, which is often associated with T-cell inflammation, is essential for successful immunotherapy. YTHDF1 can be used in combination with emerging checkpoint inhibitors or dendritic cell vaccines as therapeutic targets for immunotherapy.

The researchers said that it will be interesting to test how human systems work together with potential dendritic cell vaccines or small molecule inhibitors that may inhibit the activity of YTHDF1 in human cancer patients.

There haven't seen any measurable toxicity, which we know is the same as YTHDF1 in mice. At this point, it seems like a very benign system. The researchers hope to start early testing within a year.