How a Little-Known Glycoprotein Blocks a Cancer Cell’s Immune Response

Targeting this inside-the-cell checkpoint could potentially improve response to cancer immunotherapy.

11:00 AM

Author | Nicole Fawcett

Interaction between STC1 and CRT within a cell

It was an unexpected discovery that started with an analysis of more than 1,000 genes. The question: why game-changing cancer immunotherapy treatments work for only a fraction of patients.

The analysis shone a light on one that popped up repeatedly in patients and mouse models that did not respond to immune checkpoint therapy: stanniocalcin-1, a glycoprotein whose role in both tumors and immunology is largely unknown.

By following the trail from this surprising thread, a University of Michigan Rogel Cancer team uncovered how stanniocalcin-1, or STC1, works inside the cell to block a cellular "eat-me" signal that typically triggers the immune system to produce T cells to fight the tumor. The findings, published in Cancer Cell, provide a potential target to improve immune responses to cancer.

MORE FROM THE LAB: Subscribe to our weekly newsletter

"We believe STC1 is a checkpoint inside the cell. It's an eat-me blocker – it blocks macrophages and dendritic cells to eat dying or dead cancer cells. We think that if we can target the STC1 pathway, it would release the blocked eat-me signal," says study senior author Weiping Zou, M.D., Ph.D., Charles B. de Nancrede Professor of Pathology, Immunology, Biology, and Surgery at the University of Michigan.

Zou and colleagues were drawn to STC1 in part because so little was known about its role in cancer. This provided a potentially interesting opportunity, but also some difficulty as they had to start at the very beginning to understand whether STC1 was causing the poor immune response or whether it was just a bystander.

They embarked on a lengthy process, first showing that STC1 was linked with low activation of T cells and worse survival in melanoma patients treated with immunotherapy. They checked against the Cancer Genome Atlas database and found high levels of STC1 tied to worse survival in 10 different cancer types. The finding also panned out in mouse models.

SEE ALSO: New Connections Reveal How Cancer Evades the Immune System

From there, the researchers used mouse models to show that STC1 within tumors was dampening the anti-tumor T cell response by impairing the antigen presenting cells, which are essential for triggering T cells. They showed that tumor STC1 was stopping the process of macrophages, a type of antigen presenting cell, from eating dying tumor cells – a process key to presenting antigen to T cells and activating them.

Specifically, the tumor STC1 traps a key eat-me signal called calreticulin, or CRT. Without sufficient surface CRT, the macrophages won't efficiently eat the dead tumor cells. Unblock the CRT and it unblocks this process. This suggests that targeting the interaction between STC1 and CRT might be a path toward making immunotherapy more effective.

It's an unusual mechanism. Most immune checkpoint therapies are based on direct surface interactions with T cells.

"What we are talking about is before anything has happened. Before the T cells were activated, the tumors have already implemented strategies so they cannot be captured. This may be why some patients are resistant to immunotherapy: their tumors express too much STC1. When you block the eat-me signal, the antigen presenting cells cannot do their job," Zou says.

Targeting the STC1 and CRT interaction inside the cell is trickier than if it were on the cell surface. It means a typical antibody approach will not work. Instead, Zou and colleagues are investigating whether they can develop a small compound that would penetrate the cell and interfere with the STC1-CRT interaction.

Like Podcasts? Add the Michigan Medicine News Break on iTunes or anywhere you listen to podcasts.

Additional authors include Heng Lin, Ilona Kryczek, Shasha Li, Michael D. Green, Alicia Ali, Reema Hamasha, Shuang Wei, Linda Vatan, Wojciech Szeliga, Sara Grove, Xiong Li, Jing Li, Weichao Wang, Yijan Yan, Jae Eun Choi, Gaopeng Li, Yingjie Bian, Ying Xu, Jiajia Zhou, Jiali Yu, Houjun Xia, Weimin Wang, Ajjai Alva, Arul M. Chinnaiyan and Marcin Cieslik.

Funding for this work was from National Cancer Institute grants CA248430, CA217648, CA123088, CA099985, CA193136, CA152470 and P30CA46592.

Paper cited: "Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance," Cancer Cell. DOI: 10.1016/j.ccell.2020.12.023


More Articles About: Lab Report Cancer Research Cancer: Help, Diagnosis & Treatment
Health Lab word mark overlaying blue cells
Health Lab

Explore a variety of health care news & stories by visiting the Health Lab home page for more articles.

Media Contact Public Relations

Department of Communication at Michigan Medicine

[email protected]

734-764-2220

Stay Informed

Want top health & research news weekly? Sign up for Health Lab’s newsletters today!

Subscribe
Featured News & Stories cancer cells microscope blue green
Health Lab
Certain gene signaling rewires tumors after immunotherapy
For some patients, immunotherapy furthers tumor progression instead of halting it. What distinguishes those who benefit from those who don’t?
Multicolored rainbow brain cross section on black background
Health Lab
New clues toward treating pediatric brain tumors harboring epigenetic mutation
Inhibition of STAT3 signaling may improve survival in those with H3.3G34R/V mutant gliomas, animal studies suggest.
 Metformin Molecular Model
Health Lab
Common diabetes drug promising against rare childhood brain tumor in laboratory studies
What if a common diabetes medication could help fight a rare type of childhood brain cancer? Recent lab studies reveal metformin shows promising results in suppressing specific tumor types.
doctor and researchers in lab coat and white coat in lab looking at syringe injection
Health Lab
Researchers uncover way to harness the power of immunotherapy for advanced prostate cancer
A protein called PIKfyve impacts multiple processes involved in metabolism and cell death; blocking it is key to making immunotherapy work in prostate cancer.
cancer cell in orange under microscope
Health Lab
Researchers Discover First Immune Stimulating Long Noncoding RNA Involved in Body's Response to Cancer
The findings in human cells and animal models suggest potential approaches to improve immunotherapy treatment against cancer.
Health Lab
New Clues to Classic Cancer Target Found in Immune Cells
Scientists have long sought to target the interaction between the proteins p53 and Mdm2 in tumor cells, but their interaction in immune cells may be just as important.