NK cell exhaustion in melanoma

The contribution of NK cells to containing tumor growth is supported by observations that NK cell infiltration in tumor tissue correlates with better prognosis. However, NK-cell based cancer therapies have lead to disappointing results so far. The development of NK cell “exhaustion” could explain the failure of NK cells to contain tumor growth in advanced cancers. Dr. Silva and Dr. Gallois have now obtained strong evidence that NK cell dysfunction develops progressively in patients with late stage melanoma. They also demonstrated for the first time that Tim-3, an inhibitory receptor, is over-expressed in exhausted NK cells from advanced melanoma patients, and that its blockade reverses this exhausted phenotype and improves NK cell function. These results reinforce the concept that Tim-3 is a promising therapeutic target, which if blocked, has the potential to produce durable clinical responses that are dependent not only upon T cells but also the innate immune system.

Dr. Gallois and Dr Silva are now interested in unraveling mechanisms of cellular exhaustion with respect to NK cells. They are also working on characterization of NK cell exhaustion in murine models of melanoma to undertake preclinical studies and determine whether NK cell exhaustion can be reversed in vivo through blockade of Tim-3 and/or other relevant molecules.

Ines Silva, MD and Anne Gallois, PhD

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