Reverse signaling via PD-L1 supports malignant cell growth and survival in classical Hodgkin lymphoma

Shahrzad Jalali, Tammy Price-Troska, Cole Bothun, Jose Villasboas, Hyo Jin Kim, Zhi Zhang Yang, Anne J. Novak, Haidong Dong, Stephen M. Ansell

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Treatment with programmed death-1 (PD-1) blocking antibodies results in high overall response rates in refractory and relapsed classical Hodgkin lymphoma (cHL) patients, indicating that PD-1/PD-1 ligand interactions are integral to progression of this disease. 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–Sternberg (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.

Original languageEnglish (US)
Article number22
JournalBlood cancer journal
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology

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