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A team from the University of Oxford has visualised how key cells of the immune system lock onto cancerous or infected cells to destroy them. The work was led by the Mike Dustin’s group at the Kennedy Institute of Rheumatology and experts in colorectal and ovarian cancers from across Oxford and computational biologists at the University of Birmingham.

T cell

CD2 was one of the first molecules to be identified on the surface of T cells. The connection of thousands of molecules of CD2 on T cells to thousands of CD58 molecules on target cells facilitates destruction of cancerous and infected targets. The new work, published in Nature Immunology shows how the exact number of these molecular connections controls the process and how reductions of these numbers may undermine the immune response to cancer.

Dustin’s team first investigated the number of CD2 molecules on T cells controls the efficiency of T cell sensing of potential targets through a striking ‘CD2 corolla’, which they could visualize using advanced microscopy.  They then found that the T cells responsible for cancer killing had lower numbers of CD2 molecules in most colorectal and ovarian tumours that needed to be removed surgically.  The inability of the patients T cells to form the CD2 corolla in the tumour may have contributed to disease progression.

CD2 corolla (green) formation at the interface between a live T cell and an artificial APC. The blue and red colours map locations of other interactions - an integrin and the T cell antigen receptor, respectively.CD2 corolla (green) formation at the interface between a live T cell and an artificial APC. The blue and red colours map locations of other interactions - an integrin and the T cell antigen receptor, respectively.

Lead author Professor Michael Dustin, of the Kennedy Institute said: “Understanding why the potentially lifesaving T cells have low CD2 in tumours may help us understand why the immune system sometimes fails to control cancer and how we might help the patient's immune system fight cancer better by boosting CD2 expression."

The findings also provide a framework to interpret the significance of CD2 expression in different contexts and the role it plays in disease.

“CD2 has been associated with immune diseases, but we were keen to investigate it in the context of cancer, because some recent studies suggest that tumour cells have the capability to alter the expression of its ligand,” said Enas Abu Shah, Reseach Fellow at the Kennedy Institute. “We used a combination of our own experiments, and publicly available datasets to measure the CD2 expression and behaviour in lung, melanoma, endometrial, ovarian and colorectal cancers.”

They found that CD2-CD58 interaction impacts the function of “checkpoint” PD1. Checkpoints are molecules on T lymphocytes that blunt the immune response to protect against collateral damage from over-aggressive immune responses.  Cancer and viruses can exploit checkpoints to stop immune responses that could be helpful.  The CD2 corolla helps balance effects of checkpoints like PD1 and thus allow more effective anti-cancer immune responses.

“The CD2 corolla works as a bull horn to instruct the T cells response but this effect is muffled by PD1,” explained Mike. “The killer T cells in several tumours we examined have low CD2 so it’s even easier to PD1 to keep T cells quiet in tumours.

“The new findings might pave the way for the next stage of therapeutics targeting CD2. One of the options may be adoptive cell therapy to target the signalling molecules such as CD2 in cancer patients to boost T cell function in the tumour macroenvironment,” he concluded.