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Researchers at the German Cancer Research Center (DKFZ) have identified a membrane protein on the surface of cancer cells that supports and stabilizes an important factor involved in T-cell activation, thus potentially improving the anti-tumoral immune response.

In recent years, Immune checkpoint inhibitors such as the anti-PD-L1 antibody nivolumab have become increasingly effective options for the treatments of several cancers. Unfortunately, in some cases a lack of stimulatory co-signals for T cells can lead to an unsuccessful immunotherapy outcome. 

One important signal for T cell activation is the co-stimulatory protein CD58. By binding to its receptor on an immune cell, an inflammatory signal is received leading to an improved response against tumors. Reporting in Cancer Cell, researchers have now found a protein expressed on the membrane of cancer cells known as CMTM6 that is able to interact with and positively regulate CD58.

“It is intriguing to observe that many cancer cells inherently express CD58, a molecule that essentially contradicts their own survival when they come under immune attack. We therefore wanted to understand what controls the expression of CD58,” said Chong Sun, PhD, immunologist at the DKFZ and co-author of the study.

According to the researchers, CMTM6 surprisingly also interacts with PD-L1—a T cell blocking receptor expressed on cancer cells targeted by most checkpoint inhibitor treatments. In the study CMTM6 protected PD-L1 from degradation while simultaneously stabilizing CD58.

“It is fascinating that CMTM6 controls two important players in our immune system, CD58 and PD-L1, even though they have opposing functions. And what is more interesting is that when we dive into the analysis of tumor samples from patients who received ICI therapies, it appears that CD58 might just take a leading role in shaping the response, in most cases,” explained Beiping Miao, PhD, postdoctoral researcher at DKFZ and first-author of the study.

To further understand CD58s role in anti-tumor immunity, the scientists used a model of T-cell receptor (TCR) treatment in a cell culture dish. Using this model, they were able to show that a loss of CMTM6 impairs T cell activation suggesting the importance of the protein in immunity.

Using mice containing grafted human leukemia cells, the team also demonstrated that a lack of CMTM6 proteins, protected cancer cells from CAR-T therapy. In human cancer cells from tumor biopsies, the researchers observed widespread expression of both CMTM6 and CD58 proteins, with higher levels correlating to a better immunotherapy response.

“Our findings highlight the importance of CMTM6 and CD58 expression in cancer cells during an immune response against tumors. Our next step is to explore the possibility of adjusting their expression in laboratory experiments. Our goal is thereby finding a way to improve cancer immunotherapies,” Sun concluded in a press statement.

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