Scientists Unveil CD58’s Role in Enhancing Immune Response Against Cancer

Researchers from the German Cancer Research Center (DKFZ), in collaboration with the Netherlands Cancer Institute, have unveiled an unexpected function of a membrane protein found on cancer cells.  CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression were previously unclear.

Immune checkpoint inhibitors (ICI) are widely used in cancer treatment. These therapies involve blocking inhibitory immune checkpoint proteins, such as PD-L1. However, the absence of stimulatory signaling can limit the effectiveness of these treatments for many cancer patients.

T cells play a pivotal role in the immune defense against tumors, and their activation is controlled by various inhibitory and stimulatory immune checkpoints. Unfortunately, cancer cells often manipulate the expression of checkpoint proteins to evade the immune system.

One such activity-promoting co-stimulatory protein is CD58. When CD58 binds to its receptor on an immune cell, it sends a stimulatory signal. Disrupting this binding can hinder the immune response against numerous cancers.

The DKFZ researchers identified that the membrane protein CMTM6 interacts with and positively regulates the expression of CD58. Surprisingly, CMTM6 also interacts with PD-L1, the primary inhibitory immune checkpoint molecule targeted by most ICI therapies. CMTM6 safeguards PD-L1 from degradation and similarly stabilizes CD58. This mechanism can potentially fine-tune the immune response.

Additionally, the team demonstrated in the study published in Cancer Cell that CMTM6 loss from tumor cells impairs T cell activation and influences the response to PD-L1 blockade. They observed that CD58 might play a significant role in shaping the response to immunotherapies in most cases.

In mice with human leukemia cell grafts, the loss of CMTM6 protected cancer cells from CAR-T cell therapy. In human cancer cells from tumor biopsies, the widespread expression of CMTM6 and CD58 correlated with a better response to immunotherapies.