Cader and Hu et al. used TCRseq and CyTOF to profile the immune environment in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) in response to PD-1 blockade (Nivolumab). The TCR repertoire was low at baseline, but responders had an expansion of clonally diverse CD4+, but not CD8+, T cells, and CD4+GrB+PD-1+ Th1 effector memory cells after therapy. Higher levels of NK cells, B cells, and a novel CD3-CD68+CD4+GrB+ monocyte population were also associated with therapy response. This suggests that in this MHC-II+ cancer type, PD-1 blockade activates both clonally diverse CD4+ T cells and innate effectors.
Contributed by Maartje Wouters
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 CD3-CD68+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.