Scientists Crack Cancer’s Hidden Defense With a Breakthrough Protein Discovery

Scientists have discovered a key protein that helps cancer cells avoid detection by the immune system during a type of advanced therapy.

By creating a new drug that blocks this protein, researchers hope to make cancer treatments more effective, especially for hard-to-treat blood cancers. This breakthrough could lead to better survival rates and fewer relapses for patients.

Scientists at City of Hope, one of the leading cancer research and treatment centers in the U.S., have uncovered a key factor that allows cancer cells to evade CAR T cell therapy.

CAR T cell therapy is an advanced cancer treatment that trains the immune system to find and destroy tumor cells. It is commonly used for certain types of leukemia and lymphoma, both of which are blood cancers. However, some cancer cells have developed ways to hide from the immune system, making the treatment less effective. A new study published today (December 17) in the journal Cell could pave the way for more personalized therapies that improve patient outcomes.

Researchers identified a protein called YTHDF2, which plays a critical role in helping blood cancer cells survive and spread. In response, City of Hope developed a new drug compound called CCI-38. This compound targets and suppresses YTHDF2, slowing the growth of aggressive blood cancers and increasing the chances of successful treatment.

“We believe that using CCI-38 to target YTHDF2 will significantly enhance the effectiveness of CAR T cell therapy on blood cancer cells,” said Jianjun Chen, Ph.D., Simms/Mann Family Foundation Chair in Systems Biology and the director of the Center for RNA Biology and Therapeutics at Beckman Research Institute of City of Hope.

“One of the challenges in treating blood cancers is a phenomenon called ‘antigen escape.’ A key target for these therapies is a protein called CD19 found on the cancer cells,” added Dr. Chen, corresponding author of the new study.

However, in 28-68% of cases, the cancer cells lower or lose this CD19 marker, making treatments less effective. Although researchers are working on strategies to target multiple components, nearly half of patients are still affected by this issue.

YTHDF2 switches on genes that help cancer cells produce a stable energy source to fuel the cells’ ability to grow and spread. Moreover, this protein helps cancer cells conceal themselves by reducing the presence of antigen biomarkers that normally trigger the immune system to detect and attack cancer. Lastly, excess YTHDF2 works like a werewolf’s bite to transform blood cells from healthy to cancerous in mouse studies.

“Reducing the need for follow-up treatments could lead to better long-term survival and less relapse for our patients while lowering side effects and medical costs,” said Xiaolan Deng, Ph.D., an associate research professor in systems biology at Beckman Research Institute of City of Hope and a co-corresponding author of the study.

City of Hope, a recognized leader in CAR T cell therapies for glioblastoma and other cancers, has treated more than 1,600 patients since its CAR T program started in the late 1990s. The institution continues to have one of the most comprehensive CAR T cell clinical research programs in the world.

“Unraveling the biology underlying YTHDF2’s function will help us develop new strategies to prevent tumor cells from escaping immune surveillance,” said Zhen-Hua Chen, Ph.D., a staff scientist in systems biology at Beckman Research Institute of City of Hope and first author of the study. “This could lead to personalized approaches for patients whose blood cancers don’t respond to initial treatment or who relapse after initial response to T cell-based immunotherapy.”

The City of Hope team has filed a patent application covering critical aspects of this work, which holds implications for improving care for patients with other cancers and severe autoimmune diseases. The next phase of research will focus on improving CCI-38’s safety and effectiveness, exploring new methods to drive YTHDF2 out of cancer cells, and developing clinical trials.

Reference: “YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies” by Zhenhua Chen, Chengwu Zeng, Lu Yang, Yuan Che, Meiling Chen, Lillian Sau, Bintao Wang, Keren Zhou, Yu Chen, Ying Qing, Chao Shen, Tingjian Zhang, Mark Wunderlich, Dong Wu, Wei Li, Kitty Wang, Keith Leung, Miao Sun, Tingting Tang, Xin He, Lianjun Zhang, Srividya Swaminathan, James C. Mulloy, Markus Müschen, Huilin Huang, Hengyou Weng, Gang Xiao, Xiaolan Deng and Jianjun Chen, 17 December 2024, Cell.
DOI: 10.1016/j.cell.2024.11.007

The Cell study “YTHDF2 promotes ATP synthesis and immune-evasion in B-cell malignancies,” was supported by a National Institutes of Health grant (P30CA33572), multiple NIH R01 grants to Dr. Jianjun Chen(CA280389, CA271497, CA243386, CA214965, CA236399 and CA211614), and funding from the Simms/Mann Family Foundation.

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