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Given the genetically driven increased PD-L1\/2 expression in HL, we hypothesized that reverse signaling through PD-1 ligands may be a potential mechanism contributing to the growth and survival of Hodgkin Reed\u2013Sternberg (HRS) cells in cHL. Our data show that engagement of PD-L1 using an agonistic monoclonal antibody increases cell survival and proliferation and reduces apoptosis in HL cell lines. We show that HL patients have significantly higher serum levels of soluble PD-1 than healthy controls, and find that both membrane-bound and soluble forms of PD-1 are able to induce PD-L1 reverse signaling in HL cell lines. PD-L1 signaling, which is associated with activation of the MAPK pathway and increased mitochondrial oxygen consumption, is reversed by PD-1 blockade. In summary, our data identify inhibition of reverse signaling through PD-L1 as an additional mechanism that accounts for clinical responses to PD-1 blockade in cHL.<\/jats:p>","DOI":"10.1038\/s41408-019-0185-9","type":"journal-article","created":{"date-parts":[[2019,2,19]],"date-time":"2019-02-19T09:06:38Z","timestamp":1550567198000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Reverse signaling via PD-L1 supports malignant cell growth and survival in classical Hodgkin lymphoma"],"prefix":"10.1038","volume":"9","author":[{"given":"Shahrzad","family":"Jalali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Price-Troska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cole","family":"Bothun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Villasboas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo-Jin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Zhang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne J.","family":"Novak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidong","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Ansell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,19]]},"reference":[{"key":"185_CR1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s13045-017-0474-3","volume":"10","author":"CY Ok","year":"2017","unstructured":"Ok, C. 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