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Resistance to immunotherapy is a frequent problem in the treatment of cancer patients. Why do some people not respond to treatments? A Toulouse-based research team has identified a mechanism responsible for resistance to immunotherapy: CD226.


Resistance to immunotherapy

In contrast with chemotherapy or radiotherapy, which directly attack tumor cells, immunotherapy mobilizes the cancer patient’s own immune defenses so that they can destroy cancer cells.

A variety of studies conducted in recent years have demonstrated the role of certain substances in the stimulation of the anti-tumor capacities of certain cytotoxic T cells. These killer lymphocytes are capable of differentiating between normal cells and cancer cells. This type of treatment therefore offers promising potential for cancer patients, even those diagnosed at an advanced stage. Moreover, numerous very effective treatments have been developed in recent years, such as immunomodulators, commonly known as monoclonal antibodies. These are checkpoint-blocking antibodies developed in the laboratory that trigger a targeted response to an immune system attack by suppressing tumor-induced immune system inhibition mechanisms.

When these treatments work, they can extend the life expectancy of cancer patients by several years or, in some cases, even cure them completely. Unfortunately, some patients do not respond to these treatments and develop resistance to immunotherapies. Research is being carried out aimed at elucidating the mechanisms underlying this resistance and increasing the response rate to immunotherapies.


CD226, a key substance underpinning the efficacy of immunotherapy

The publication of a recent study conducted by a team of scientists in Toulouse opens up some promising avenues in the field of immunotherapy.1 According to the researchers, CD226 is essential for correct killer cell function, enabling them to recognize and destroy cancer cells. The scientists believe that the expression of this functional protein - CD226 - is an essential prerequisite for the reactivation of T cells in the context of immunological treatment.

The researchers reached this conclusion after studying a sample of 177 patients with various cancers. They observed that CD226 was frequently absent from the surface of the natural killer cells of cancer patients. They believe that the absence of this protein in some patients may partially explain the phenomenon of resistance to immunotherapy. This absence may be one of the main causes of cytotoxic T cell malfunction and, consequently, the failure of immunological treatments for some types of cancer, including breast, lung and liver cancer, in particular. By discovering this key mechanism underpinning the effectiveness of immunotherapies, the research will make it possible both to predict the response to immunological treatments in cancer patients and to develop new treatments, with the aim of curing a greater number of cancer patients.



  1. Weulersse M, Asrir A, Pichler AC, Lemaitre L, Braun M, Carrié N, Joubert MV, Le Moine M, Do Souto L, Gaud G, Das I, Brauns E, Scarlata CM, Morandi E, Sundarrajan A, Cuisinier M, Buisson L, Maheo S, Kassem S, Agesta A, Pérès M, Verhoeyen E, Martinez A, Mazieres J, Dupré L, Gossye T, Pancaldi V, Guillerey C, Ayyoub M, Dejean AS, Saoudi A, Goriely S, Avet-Loiseau H, Bald T, Smyth MJ, Martinet L. Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy. Immunity. 2020 Oct 13;53(4):824-839.e10. doi: 10.1016/j.immuni.2020.09.006. PMID: 33053331.