How a little-known glycoprotein blocks a cancer cell's immune response

January 28, 2021

ANN ARBOR, Michigan -- 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.

"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.

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.
-end-
Additional authors: 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, Marcin Cieslik

Funding: National Cancer Institute grants CA248430, CA217648, CA123088, CA099985, CA193136, CA152470, P30CA46592

Disclosure: None

Reference: Cancer Cell, doi: 10.1016/j.ccell.2020.12.023

Resources: University of Michigan Rogel Cancer Center, http://www.rogelcancercenter.org Michigan Health Lab, http://www.MichiganHealthLab.org Michigan Medicine Cancer AnswerLine, 800-865-1125

Michigan Medicine - University of Michigan

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.