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Consequently, the focus has shifted to targeting alternative inhibitory receptors (<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>s) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene\u20103 (<jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3) (<jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>223) is the third <jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content> to be targeted in the clinic, consequently garnering considerable interest and scrutiny. <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3 and interplay with other <jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>s remain largely unknown. However, the striking synergy between <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3 and <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3 as compared with other <jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>s, highlights the potential uniqueness of <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3. There are now four <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3\u2010targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this <jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>. Given the translational relevance of <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3 and the heightened interest in the impact of dual <jats:styled-content style=\"fixed-case\">LAG<\/jats:styled-content>3\/<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly increasing or dampening enthusiasm for subsequent targets in the cancer immunotherapeutic pipeline.<\/jats:p>","DOI":"10.1111\/imr.12519","type":"journal-article","created":{"date-parts":[[2017,3,4]],"date-time":"2017-03-04T13:15:43Z","timestamp":1488633343000},"page":"80-96","source":"Crossref","is-referenced-by-count":891,"title":["<scp>LAG<\/scp>3 (<scp>CD<\/scp>223) as a cancer immunotherapy target"],"prefix":"10.1111","volume":"276","author":[{"given":"Lawrence P.","family":"Andrews","sequence":"first","affiliation":[{"name":"Department of Immunology University of Pittsburgh School of Medicine  Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel E.","family":"Marciscano","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology &amp; Molecular Radiation Sciences Sidney Kimmel Comprehensive Cancer Center The Johns Hopkins School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles G.","family":"Drake","sequence":"additional","affiliation":[{"name":"Departments of Oncology, Immunology and Urology Sidney Kimmel Comprehensive Cancer Center The Johns Hopkins School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario A. 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