Cancer immunotherapy -- a way for the immune system to recognize and kill cancer cells -- has revolutionized the treatment of many cancer types. For example, approximately 40% of melanoma patients respond to immunotherapy, allowing T cells in the immune system to attack cancer cells and hence control disease.

In a new study, researchers from the Chinese Academy of Sciences, Tsinghua University, and the University of Chicago in the United States confirmed that they were able to increase the tumor control rate from about 40% to nearly 100% by initiating a parallel pathway. The results of the study were published online February 6, 2019 in the journal Nature, titled "Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells". The authors of the paper are Dr. Meng Michelle Xu from Tsinghua University School of Medicine, Tsinghua University Institute of Immunology, Dr. Dali Han from the Beijing Institute of Genomics, Chinese Academy of Sciences, and Dr. Chuan He from the Institute of Biophysical Dynamics, University of Chicago.

This new study relies on manipulation of dendritic cells, which are important components of the immune system. Their primary function is to process antigens and present them to T cells. In addition, they act as messengers and will link the innate immune system to the adaptive immune system.

However, a protein called YTHDF1 affects the processing of antigen by dendritic cells. This protein was discovered and identified by Dr. Chuan He in 2015. YTHDF1 controls the level of protease that destroys potential tumor antigens. This limits their presentation to T cells.

As a matter of fact, this limitation presents a problem. However, when these researchers cleared YTHDF1 in dendritic cells, these cells enhanced their ability to phagocytose antigenic peptides, degrading them and presenting them to T cells. This opens up a new and potentially effective treatment for cancer in patients who have poor response to immune checkpoint inhibitors.

The researchers said that when they used the YTHDF1 knockout and the immunological checkpoint inhibitor anti-PD-L1 at the same time, they achieved almost complete tumor control in the mouse model. The melanoma mouse model that received the YTHDF1 knockout respond to anti-PD-L1 by 100% instead of 40%.

These researchers confirmed that mouse dendritic cells lacking YTHDF1 are more effective in antigen presentation than dendritic cells from normal wild-type mice. Dr. Dali Han said, "Our data show that deletion of YTHDF1 in dendritic cells reduces antigen degradation, leading to better cross-presentation and cross-activation of CD8+ T cells."

In addition, these researchers performed additional tests using biopsies from colon cancer patients, where colon cancer responded much greater to immunotherapy than melanoma. They found that tumor tissue from patients with high levels of YTHDF1 suffered from limited T cell infiltration, but tumor tissue from patients with low levels of YTHDF1 suffered more T cell infiltration. This indicates that there is a good correlation between human and mouse experimental data.

A long-standing yet important question in cancer treatment is how can people achieve better antigen presentation? This study opened many doors and provides a whole new set of targets for the immune system: from a range of new antigens to potential anti-cancer vaccines.

These researchers point out a view that decreased levels of YTHDF1 are generally consistent with the T cell inflammatory tumor microenvironment, which is critical for successful immunotherapy. YTHDF1 may be a therapeutic target for immunotherapy in conjunction with emerging immunological checkpoint inhibitors or dendritic cell vaccines.

Dr. Meng Michelle Xu said, "It will be very interesting to test how the human system works with potential dendritic cell vaccines or small molecule inhibitors that inhibit YTHDF1 activity in human cancer patients."

Dr. Chuan He added, “We have not observed any measurable toxicity associated with knocking out YTHDF1 in mice so far. In this regard, this seems to be a very good system. We hope that early testing in patients could begin within this year."

Examples of immune checkpoint proteins (targets) found on T cells or cancer cells include:

• IDO1• TDO• PD-1• PD-L1• CTLA4• KIR• 4-1BB(also known as CD137)• OX40 (also known as CD134)• LAG3• B7‑H3(also known as CD276)• TIM3• TIGIT• BTLA• VISTA• ICOS• CD39• CD27• CD30(also known as TNFRSF8)• CD28• B7-H4(also known as B7‑S1, B7x and VCTN1)• HHLA2• Galectins• CD155

Author's Bio: 

This article is written by scientists from BOC Sciences, a chemical company specialized in supplying inhibitors (such as IDO inhibitors), impurities, metabolites and many other chemicals that are needed by researchers for multiple use.