Cancer Immunotherapy

Marina Lebedeva

Scientists from the German Cancer Research Centre (DKFZ) have discovered a new function of a membrane protein on the surface of cancer cells: it maintains and stabilises an important “co-stimulatory” factor that enhances the activation of T cells, thereby improving the immune response against the tumour. The study was conducted in collaboration with researchers from the Netherlands Cancer Institute.

Many types of cancer can be successfully treated using immune checkpoint inhibitors (ICIs), which is a form of immunotherapy. The basis of this method is to block inhibitory immune checkpoint proteins such as PD-L1. However, the absence of a stimulating signal may render such therapies ineffective. This is one reason many cancer patients do not benefit from immune checkpoint inhibitors.

T lymphocytes play a key role in immune defence against tumours. Their activation is tightly regulated by various inhibitory and stimulatory immune checkpoints. However, tumour cells often disrupt this system by manipulating the expression of checkpoint proteins to avoid attack by the immune system.

Among the proteins that promote activation, CD58 stands out. When it binds to a receptor on an immune cell, it results in the transmission of a stimulatory signal. If CD58's binding to its receptor is blocked, the immune response against many cancers is weakened.

"It's interesting that many cancer cells intrinsically express CD58, a molecule that is essentially at odds with their own survival when they are attacked by the immune system. So we wanted to understand what regulates CD58 expression," said Chong Sun, an immunologist at the German Centre for cancer research.

According to the results of recent studies, scientists have found that the membrane protein CMTM6 interacts with CD58 and contributes to its positive regulation. A surprising fact is that CMTM6 simultaneously interacts with PD-L1, an important inhibitory molecule in immune control that is the target of most current immune checkpoint inhibitor therapies. This mechanism may tune the immune response.

"Interestingly, CMTM6 regulates two key players in our immune system, CD58 and PD-L1, despite their opposing functions. And more importantly, in more in-depth analysis of tumour samples from patients treated with immune checkpoint inhibitor therapy, CD58 may play a role a leading role in shaping the response, in most cases,” explains Beiping Miao , one of the authors.

Using mice transplanted with human leukaemia cells, the research team demonstrated that loss of CMTM6 makes cancer cells resistant to CAR-T therapy. Additionally, analysis of human cancer cells from tumour biopsies revealed high expression levels of CMTM6 and CD58, which were correlated with more effective response to immunotherapy.

"Our results highlight the importance of the expression of CMTM6 and CD58 in cancer cells during the immune response against tumours. Our next step is to explore the possibility of regulating their expression in laboratory experiments. We aim to find ways to improve cancer immunotherapy," said Sun.

- Pravda.ru