Removing melanoma's cloak of immune invisibility

Melanoma cells are able to evade cancer immunotherapy by using a specific protein to hide from immune system T cells out to seek and destroy them.

“We found that MEX3B abolishes antigen presentation on tumor cells so they can’t be recognized by T cells. If they can’t be recognized, they can’t be killed,” says Lu Huang, Ph.D., a postdoctoral fellow in the lab of Patrick Hwu, M.D., chair of Melanoma Medical Oncology at MD Anderson, and lead author of a paper in Clinical Cancer Research.

Cancer immunotherapy works to activate the body’s immune system against cancer and has shown promising outcomes in some melanoma patients, but many do not respond. Understanding how tumors resist is key to overcoming that resistance and extending strong responses to more patients.

Huang and colleagues searched for genes involved in resistance to immunotherapy using melanoma cell lines and T cells developed from tumors of metastatic melanoma patients. They first analyzed the effect of 384 protein kinases on the tumor-killing ability of T cells primed to attack the disease.

After identifying the top 20 proteins proficient at hindering T cells, the team searched through a public database containing gene expression levels in melanoma patients treated with anti-PD-1 checkpoint blockade drugs, which inhibit a protein on T cells called PD-1 that shuts down immune response.

Among those proteins, only MEX3B, part of the muscle excess 3 family of proteins, was shown to be differentially expressed in patients who did not respond to anti-PD-1 immunotherapy compared to responders. Higher MEX3B expression also is associated with worse response to treatment.

“We then measured interferon gamma release by T cells, which is an indication of how well T cells recognize tumors,” Huang says. Tumors with high expression of MEX3B faced a dramatic drop in interferon gamma release.

With the association established, the next question was how MEX3B was reducing T-cell recognition and attack of tumor cells. The team found an important connection: Tumor cells with high MEX3B expression had drastically reduced levels of the HLA-A (human leukocyte antigen A) protein on their cell surfaces.

Knocking down HLA-A to hide from T cells

HLA proteins are crucial components for the major histocompatibility complex, regulating immune response by presenting peptides that are drawn from inside the cell out onto the surface for examination by the immune system. T cells check these peptides (antigens), and when they are markers of infection or cell damage, the T cells kill the cell.

There are three major HLA proteins, A, B and C, of which HLA-A is the predominant version responsible for antigen presentation in melanoma. With HLA-A loss, antigens aren’t presented, so T cells can’t attack.  

“It was important to identify the mechanism by which MEX3B inhibits HLA-A,” Huang says.

MEX3B is an RNA-binding protein that regulates gene expression by binding to and disrupting messenger RNA (mRNA). The team found that MEX3B destabilizes HLA-A by binding to a specific region of its mRNA.

With the culprit identified, the next step is finding ways to thwart it by developing a MEX3B-targeting drug to use in combination with checkpoint blockade or other immunotherapies.

“MEX3B is not expressed on the tumor surface, so it’s not possible to design antibodies against it,” Huang says. “We will have to develop small-molecule inhibitors or short interfering RNAs to target MEX3B.”