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GUT. Strategy revealed that allows the most aggressive pancreatic cancer cells to evade the body’s defences

31.05.2024

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Susana García-Silva, researcher at the Spanish National Cancer Research Centre (CNIO). /Laura M. Lombardía. CNIO

The cells responsible for spreading pancreatic cancer to other organs hide among immune system cells using one of the system’s own defence proteins as a "camouflage".

This is one of the reasons why immunotherapy is not effective in pancreatic cancer. "Understanding this mechanism will facilitate the development of an immunotherapy that also works in pancreatic cancer," says Susana García-Silva, from the Spanish National Cancer Research Centre (CNIO).

The study is published in the journal Gut.

Pancreatic cancer is usually diagnosed at an advanced stage and is highly resistant to chemotherapy. Part of its aggressiveness is attributed to the fact that some of its cells, known as cancer stem cells, have the power to restart the tumour and also evade the body’s defence system. After decades of trying to understand how they do this, Spanish research groups have now revealed their strategy: pancreatic cancer stem cells evade immune cells by disguising themselves with a protein that is normally used for defence.

This finding could make it easier for immunotherapy-based treatments to also work in pancreatic cancer, according to Susana García-Silva, a researcher at the Spanish National Cancer Research Centre (CNIO): “The challenge now is to block the protein we have identified, and see if it is an effective therapy against pancreatic cancer on its own or as a combined treatment.”

“Immunotherapies, which redirect the body’s natural defences against the tumour, are currently the most effective treatment for advanced cancers. But they don’t work in pancreatic cancer,” explains García-Silva. “To be effective in pancreatic cancer, we need to understand the tumour’s immune evasion strategies, especially those of the cancer stem cells, as they are the ones that sustain tumour growth.”

García-Silva, from the CNIO’s Microenvironment and Metastasis Group, is co-author of this study, which uses animal models and patient samples and is published in the journal Gut.

Other co-authors are Juan Carlos López-Gil, from the Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), the Universidad Autónoma de Madrid (UAM) and the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM-CSIC-UAM); Bruno Sainz, from CIBERONC, IRYCIS and IIBM-CSIC-UAM; and Christopher Heeschen, from the Candiolo Cancer Institute (IRCCS), Italy, and former group leader at the CNIO.

An antibacterial protein that plays a role in cancer

Discovering the protein that pancreatic cancer stem cells use to protect themselves from immune cells was a surprising finding for García-Silva. It is called PGLYRP1 and belongs to a family of proteins found in organisms as diverse as insects and mammals, which generally means that it has been conserved throughout evolution because it plays an important role.

The new study reveals that the protein also plays a role in cancer, but in an unexpected way. The normal function of PGLYRP1 is to help the immune system respond to bacterial attack, but pancreatic cancer stem cells use the protein for a different purpose: to disguise themselves as immune system cells and hide among the very cells that are supposed to destroy them.

“It was already known that tumour cells use immune system proteins to disguise themselves and escape, but the use of a protein with anti-bacterial properties as an immuno-resistance strategy in cancer had not been described,” says García-Silva.

New therapies in development

We now know that the role of PGLYRP1 in pancreatic cancer “is very important,” says the CNIO researcher. “When a pancreatic cancer cell is alone and has to face the immune system, it needs this protein to evade it, grow and generate a tumour. PGLYRP1 is important in the early stages of tumour formation, and also for metastasis formation, which is another moment when a small number of cells face the immune system.”

“When we remove PGLYRP1 from tumour cells, we see that the immune system responds by attacking them, which prevents the primary tumour from forming and these cells from spreading and metastasising,” says Sainz. “We are now developing therapies to block or eliminate this protein in the hope that we can combine them with current treatments and attack the cancer stem cells on another front.”

Funding

The project has been funded by the La Caixa Foundation (@FundlaCaixa), the Fero Foundation (@FundacionFero), the Pancreatic Cancer Association (ACANPAN, @ACanPan), the Spanish Pancreatology Association (AESPANC, @AESPANC), the Spanish Association Against Cancer (AECC, @ContraCancerEs), the Carlos III Institute (ISCIII, @SaludISCIII) and the Ministry of Science, Innovation and Universities (MICIU), as well as the gastrointestinal tumour programme of CIBERONC.

Reference article

López-Gil JC, García[1]Silva S, Ruiz-Cañas L, et al. The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells Gut.
doi: 10.1136/gutjnl-2023-330995 

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