A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma

Fathima Zumla Cader, Xihao Hu, Walter L. Goh, Kirsty Wienand, Jing Ouyang, Elisa Mandato, Robert Redd, Lee N. Lawton, Pei Hsuan Chen, Jason L. Weirather, Ron C.J. Schackmann, Bo Li, Wenjiang Ma, Philippe Armand, Scott J. Rodig, Donna Neuberg, X. Shirley Liu, Margaret A. Shipp

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs), which exhibit frequent copy-number gains of CD274 (PD-L1) and PDC1LG2 (PD-L2) on chromosome 9p24.1. However, in this largely MHC-class-I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined. We utilized the complementary approaches of T cell receptor (TCR) sequencing and cytometry by time-of-flight analysis to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial (NCT02181738). Anti-PD-1 therapy was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton clones during treatment. CD4+, but not CD8+, TCR diversity significantly increased during therapy, most strikingly in patients who had achieved complete responses. Additionally, patients who responded to therapy had an increased abundance of activated natural killer cells and a newly identified CD3CD68+CD4+GrB+ subset. These studies highlight the roles of recently expanded, clonally diverse CD4+ T cells and innate effectors in the efficacy of PD-1 blockade in cHL.

Original languageEnglish (US)
Pages (from-to)1468-1479
Number of pages12
JournalNature medicine
Volume26
Issue number9
DOIs
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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