An international team [1], led by Dr Ludovic Martinet (Inserm researcher) and Pr Hervé Avet-Loiseau from the Toulouse Cancer Research Centre (CRCT / Inserm, University of Toulouse III – Paul Sabatier, CNRS), has just published a study in the journal Immunity which opens up prospects for improving the effectiveness of immunotherapy. The absence of one molecule in certain cancer patients, CD226, is said to be one of the keys to understanding resistance to immunotherapy.

Immunotherapy and therapeutic resistance

Even if most cancers are difficult to cure when they are diagnosed at an advanced stage, a new therapeutic strategy seems to be able to reverse the trend in recent years: immunotherapy. Instead of attacking tumour cells directly, this approach aims to stimulate the patient’s “defences”, their immune system, to fight against tumour cells.

The aim of immunotherapy is to “wake up” the patient’s immune system so that it can eliminate the cancer cells. Killer lymphocytes are the most promising immune system players against cancer.

According to the National Cancer Institute (INCa), it is estimated that there are 382,000 new cases of cancer per year in metropolitan France. With 150,000 deaths per year, cancer is the leading cause of premature mortality in France.

In recent years, researchers have been able to show that many molecules increase or slow down the anti-cancer capacities of killer lymphocytes. Several treatments that increase the destruction of cancer cells by the immune system have thus been generated, some of which have already proven to be highly effective in the treatment of cancer.

This approach is based in particular on the use of monoclonal antibodies called immunomodulators because they lift the inhibition mechanisms of the immune system induced by the tumour. These mechanisms are common to various cancers and these recent treatments already have indications in seven types of cancer: lung, kidney, bladder, head and neck, melanoma, Hodgkin’s disease and Merkel’s disease. They are currently being evaluated in many other cancers. Injected through the bloodstream, these drugs have a systemic action on primary tumours and metastases.

An analysis of 19 international studies conducted on 11,640 patients suffering from different types of cancer shows that 25% of those treated with immunotherapy showed a “lasting response”, compared with only 11% of those who received another family of treatments (chemotherapy or targeted therapy).

While these drugs are promising, they are unfortunately not effective for all patients and it is therefore necessary to identify other mechanisms that regulate the destruction of cancer cells by killer lymphocytes. Ongoing research therefore seeks to identify and extend the number of patients responding to immunotherapy.

CD226, an essential molecule

Thanks to complementary approaches, involving samples from 177 patients suffering from various cancers (lung, breast, ovary and myeloma) and experimental tumour models, the research team of Dr Ludovic Martinet and Pr Hervé Avet-Loiseau has recently identified a molecule that is essential for the functions of killer lymphocytes: CD226. It allows the killer lymphocytes to recognise the cancer cells, a necessary step in the destruction of these cells.

The work of this research team has also shown that the CD226 molecule is frequently absent on the surface of the killer lymphocytes of cancer patients.

The absence of the CD226 molecule is a brake that prevents the killer lymphocytes from functioning normally, this absence being associated with a poor prognosis in various malignant pathologies such as melanomas, breast, lung or liver cancer.

In collaboration with Australian researchers (Pr Smyth’s team, QIMR Berghofer), the Toulouse team observed that the expression of the CD226 molecule was necessary to enable immunotherapy to reactivate killer lymphocytes and the level of expression of the CD226 molecule seems to be an indicator of response to this type of treatment in metastatic melanoma. These observations therefore seem to demonstrate that the absence of CD226 represents a key mechanism of tumour resistance to the immune system. This molecule conditions the response to current immunotherapies.

An inter-institutional and international collaboration

This study is the result of collaboration between CRCT members and clinicians from the IUCT-Oncopole but also of exchanges with the Toulouse Purpan Physiopathology Centre (Inserm, University Toulouse III – Paul Sabatier, CNRS), Australian (QIMR berghofer, Brisbane) and Belgian (Brussels) researchers.

Ultimately, these discoveries could lead to the development of new treatments in order to make the action of current immunotherapies more effective and to cure a greater number of cancer patients. This also opens up prospects for other types of pathologies such as viral diseases, for which killer lymphocytes are known to be the main effectors.

1]The Toulouse Purpan Physiopathology Centre (CPTP – CNRS/University Toulouse-III – Paul-Sabatier/INSERM) and the International Centre for Research in Infectiology (CIRI – INSERM/CNRS/ENS Lyon/University Claude Bernard Lyon 1), the Mediterranean Centre for Molecular Medicine (C3M – INSERM/University Nice Sophia Antipolis, CHU de Nice and the University Institute of Cancer (IUCT) have also participated in this work.

Discover the published article :

Immunity. 2020 Oct 13;53(4):824-839.e10.doi: 10.1016/j.immuni.2020.09.006.
Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8 + T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy
Marianne Weulersse , Assia Asrir , Andrea C Pichler , Lea Lemaitre , Matthias Braun , Nadège Carrié , Marie-Véronique Joubert , Marie Le Moine , Laura Do Souto , Guillaume Gaud , Indrajit Das , Elisa Brauns , Clara M Scarlata , Elena Morandi , Ashmitha Sundarrajan , Marine Cook , Laure Buisson , Sabrina Maheo , Sahar Kassem , Arantxa Agesta , Michaël Pérès , Els Verhoeyen , Alejandra Martinez , Julien Mazieres , Loïc Dupré , Thomas Gossye , Vera Pancaldi , Camille Guillerey , Maha Ayyoub , Anne S Dejean , Abdelhadi Saoudi , Stanislas Goriely , Hervé Avet-Loiseau , Tobias Bald , Mark J Smyth , Ludovic Martinet

Contact :

Dr Ludovic Martinet
CRCT Team 13: “”Oncogenomics and immunology of myeloma””.
Mail: ludovic.martinet@inserm.fr

Partnerships :

This work was made possible thanks to the support of the ARC Foundation, the National Cancer Institute, the Cancer Research Institute (Bristol-Myers Squibb CLIP Grant) and the Toulouse cancer santé Foundation (IUCT-O translational research program).