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Yasinska IM et al. The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer. Frontiers in Immunology 10, 1594 (2019). DOI: 10.3389/fimmu.2019.01594.

Learning how breast cancer cells evade the immune system

Cancer cells have ways to evade the human immune system, but research at UK’s Synchrotron, Diamond could leave them with nowhere to hide

Announced today to coincide with World Cancer Day, the latest research (published in Frontiers in Immunology) by Dr Vadim Sumbayev, together with an international team of researchers, working in collaboration with Dr Rohanah Hussain and Prof Giuliano Siligardi at Diamond Light Source. They have been investigating the complex defence mechanisms of the human immune system and how cancer cells in breast tumours avoid it. In particular, they sought to understand one of the biochemical pathways leading to production of a protein called galectin-9, which cancer cells use to avoid immune surveillance.

Dr Vadim Sumbayev explains,

The human immune system has cells that can attack invading pathogens, protecting us from bacteria and viruses. These cells are also capable of killing cancer cells, but they don't. Cancer cells have evolved defence mechanisms that protect them from our immune system, allowing them to survive and replicate, growing into tumours that may then spread across the body. Unfortunately, the molecular mechanisms that allow cancer cells to escape host immune surveillance remain poorly understood. So, with a growing body of evidence suggesting that some solid tumours also use proteins called Tim-3 and galectin-9 and to evade host immune attack, we chose to study the activity of this pathway in breast and other solid and liquid tumours.

: Breast cancer cell-based pathobiochemical pathways showing LPHN-induced activation of PKCα, which triggers the translocation of Tim-3 and galectin-9 onto the cell surface which is required for immune escape.

The teams’ previous work at Diamond led them to conclude that the immune receptor Tim-3 and the protein it naturally binds to galectin-9, play a role in allowing acute myeloid leukaemia (AML) cells escape the human immune system. Their new work found that breast tumours express significantly higher levels of Tim-3 and galectin-9 than healthy breast tissues, with the result suggesting that both proteins are expressed by the same cells. Further experiments showed that a wide range of different cancers express detectable amounts of both Tim-3 and galectin-9.

Using an experimental model, the team were able to show that lymphocytes can attack breast cancer cells when galectin-9 is disabled. The team then investigated nine more types of cancer and found their results applicable everywhere. Tim-3 and galectin-9 are far more active in cancer cells.

Our findings demonstrate the activity of the Tim-3-galectin-9 biochemical pathway in several types of human cancer cells, as well as its possible role in the suppression of the immune system response. Our ultimate goal is now to find the best way to disable the Tim-3-galectin-9. This could lead to therapies that allow our immune systems to attack cancer, reducing the need for more toxic treatments such as chemotherapy and radiotherapy, which have severe side-effects for patients.

The team are already planning another visit to Diamond, for the next stage in this vital research. "Access to Diamond is crucial to our research. The sensitivity that synchrotron radiation allows cannot be replicated using other techniques, and it allows us to really see what's happening to the proteins, even small details," concludes Dr Sumbayev. At Diamond, the team used Synchrotron Radiation Circular Dichroism (SRCD) spectroscopy on beamline B23 to investigate the point at which the pathway begins.

Synchrotron Radiation Circular Dichroism (SRCD) Spectroscopy

At Diamond, the team used SRCD spectroscopy to investigate the point at which the pathway begins. AML cells trigger the pathway using the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine-rich transmembrane protein 3 (FLRT3).

The researchers found that primary breast tumours expressed galectin-9, Tim- 3 and FLRT3, as well as two protein variants of LPHN - LPHN2 and LPHN3. Using SRCD spectroscopy, the team were able to prove the interaction between FLRT3 and LPHN2 that triggers the immune suppressive pathway in breast cancer cells.

To find out more about the B23 beamline, or to discuss potential applications, please contact Principal Beamline Scientist Giuliano Siligardi: [email protected].

Diamond Light Source is the UK's national synchrotron science facility, located at the Harwell Science and Innovation Campus in Oxfordshire.

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