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We investigated the <jats:styled-content style=\"fixed-case\">MOA<\/jats:styled-content> of lenalidomide in clinical samples from patients enrolled in the <jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content>\u20105013\u2010<jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content>\u2010002 trial (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>00875667) comparing single\u2010agent lenalidomide <jats:italic>versus<\/jats:italic> investigator's choice single\u2010agent therapy and validated our findings in pre\u2010clinical models of <jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content>. Our results revealed a significant increase in natural killer (<jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>) cells relative to total lymphocytes in lenalidomide responders compared to non\u2010responders that was associated with a trend towards prolonged progression\u2010free survival and overall survival. Clinical response to lenalidomide was independent of baseline tumour microenvironment expression of its molecular target, cereblon, as well as genetic mutations reported to impact clinical response to the Bruton tyrosine kinase inhibitor ibrutinib. Preclinical experiments revealed lenalidomide enhanced <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell\u2010mediated cytotoxicity against <jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content> cells via increased lytic immunological synapse formation and secretion of granzyme B. In contrast, lenalidomide exhibited minimal direct cytotoxic effects against <jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content> cells. Taken together, these data provide the first insight into the clinical activity of lenalidomide against <jats:styled-content style=\"fixed-case\">MCL<\/jats:styled-content>, revealing a predominately immune\u2010mediated <jats:styled-content style=\"fixed-case\">MOA<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/bjh.14866","type":"journal-article","created":{"date-parts":[[2017,8,3]],"date-time":"2017-08-03T19:31:06Z","timestamp":1501788666000},"page":"399-409","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Activity of lenalidomide in mantle cell lymphoma can be explained by <scp>NK<\/scp> cell\u2010mediated cytotoxicity"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8577-0105","authenticated-orcid":false,"given":"Patrick R.","family":"Hagner","sequence":"first","affiliation":[{"name":"Celgene Corporation Summit NJ 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