Epstein-Barr (EBV) is a virus of the herpesvirus family, strongly associated with some epithelial tumors and B-cell lymphoma. One of the most promising therapeutic strategies for the treatment of virus-associated tumours is immunotherapy and only a more in-depth understanding of the molecular mechanisms involved will allow its extended therapeutic use.

A new study by a team of researchers of Sapienza University of Rome, published in the journal Blood, which also dedicated the cover image to this research, has discovered that the viral protein EBNA2, encoded by the Epstein-Barr virus, reduces the expression of the ICOSL protein, a crucial molecule both for the recognition of the tumour cell by the immune system and for the generation of efficient antiviral antibodies.

“Already in our previous study – highlights Eleni Anastasiadou of the Department of Clinical and Molecular Medicine at Sapienza – we had demonstrated how EBV uses the viral protein EBNA2 to increase the expression of PD-L1 on the surface of the tumour cell. Through this mechanism, EBV prevents the immune system from acting against the tumour. Now, this new study reveals a further and fundamental mechanism that deceives the immune system and promotes tumour proliferation."

“The prognosis of patients with EBNA2 positive lymphoma is very unfavourable and tracing the cause of the immune evasion was important - specifies Pankaj Trivedi of the Department of Experimental Medicine - Together with Pathologist, Carla Giordano, we asked whether the severe immunosuppression and the unfavourable prognosis could be due to reduced expression of ICOSL. Indeed, our data confirmed that intuition. We have now identified EBNA2, a viral protein as the main negative regulator of ICOSL. It does so by increasing microRNA-24. This is how the virus, and together with it, also the tumour cell, escape from immune control.”

The identification of this novel mechanism of viral immune evasion, thanks to the analysis of over a thousand cases of diffuse large B-cell lymphoma, opens up new therapeutic opportunities. By inhibiting the activity of miR-24 scientists can reestablish ICOSL expression on the tumor cell and make it again visible to the immune system.

“For the first time we have clarified in the field of virology how the Epstein-Barr virus uses one of its most important proteins to compromise immune responses - concludes Trivedi - Now we have an important tool in our hands to reconstitute ICOSL on cancer cells and our hope is that in the foreseeable future, this discovery could be clinically applied for cancer therapies".

References: 

Epstein-Barr virus-encoded EBNA2 downregulates ICOSL by inducing miR-24 in B-cell lymphoma - Martina Leopizzi, Lucia Mundo, Elena Messina, Federica Campolo, Stefano Lazzi, Antonio Angeloni, Cinzia Marchese, Lorenzo Leoncini, Carla Giordano, Frank Slack, Pankaj Trivedi, Eleni Anastasiadou

Further Information

Pankaj Trivedi
Department of Experimental Medicine
pankaj.trivedi@uniroma1.it

Eleni Anastasiadou 
Department of Clinical and Molecular Medicine
eleni.anastasiadou@uniroma1.it