Findings from a translational analysis of CheckMate 205 study indicate that anti-PD-1 therapy was most effective in patients with classical Hodgkin lymphoma (cHL) who had a diverse baseline T cell receptor (TCR) repertoire. X. Shirley Liu and Margaret A. Shipp of the Dana-Farber Cancer Institute in Boston, MA, USA and colleagues, who published their results on 10 August 2020 in the Nature Medicine, wrote that CD4+, but not CD8+, TCR diversity significantly increased during the therapy and most strikingly in patients who had achieved complete responses (CRs). In addition, the patients who responded to therapy had an increased abundance of activated natural killer (NK) cells and a newly identified CD3−CD68+CD4+GrB+ subset.
The authors wrote in the study background that cHL includes rare malignant Hodgkin Reed–Sternberg (HRS) cells mixed with abundant inflammatory and immune cells. Although the cHL inflammatory infiltrate is rich in T cells, it is not associated with an effective anti-tumour immune response.
The investigators previously identified near-universal copy-number gains of PD-L1 and PD-L2 on chromosome 9p24.1, and copy-number-dependent increased expression of the PD-1 ligands on HRS cells. PD-1 ligands engage PD-1-receptor-positive T cells and induce T cell exhaustion, which can be abrogated by PD-1 blockade.
Patients with relapsed/refractory cHL, who have a genetic basis for enhanced PD-1 signalling, also exhibit the highest reported response rates to PD-1 blockade. Multiple PD-1 antibodies have been approved for the treatment of relapsed/refractory cHL and incorporated into front line clinical trials. Despite these genetic observations and rapid clinical translation, the precise mechanism of action of PD-1 blockade in cHL remains undefined.
In certain solid tumours, PD-1 blockade increases the activity of CD8+ cytotoxic T cells in the tumour microenvironment (TME). However, HRS cells frequently lack cell-surface expression of β2 microglobulin (B2M) and major histocompatibility complex (MHC) class I owing to inactivating mutations of B2M or copy loss of B2M or MHC class I genes. As MHC-class-I-mediated tumour antigen presentation is essential for recognition by CD8+ T cells, these findings implicate non-CD8+ effector mechanisms of PD-1 blockade in cHL.
MHC-class-II-mediated antigen presentation to CD4+ effector cells also plays an important role in anti-tumour immunity. HRS cells are often MHC class II-positive, likely reflecting their lineage from MHC class II-positive B cells in the germinal centre. In intact tumours, PD-L1-positive HRS cells are also more likely to be in physical contact with PD-1-positive CD4+ T cells than with PD-1-positive CD8+ T cells. The previous single-cell analyses of primary cHL cell suspensions also revealed a CD4+ T-cell-rich TME with expanded numbers of T-helper 1-polarised effectors and regulatory T cells.
Consistent with these observations, the same team also found that expression of MHC class II, but not MHC class I, in HRS cells was associated with responses to PD-1 inhibitor nivolumab in patients with relapsed/refractory cHL. Additional evidence of non-MHC-restricted immune mechanisms came from patients who achieved short-lived CRs to anti-PD-1 blockade although their HRS cells lacked expression of β2M, MHC class I and MHC class II.
Recent studies in murine models and patients with certain solid tumours associate circulating immune cell subsets with responses to checkpoint blockade.
In this translational study, the study team utilised complementary approaches, TCR sequencing and cytometry by time-of-flight (CyTOF) analyses, to characterise the peripheral immune signature of patients with relapsed/refractory cHL who received anti-PD-1 therapy. In particular, they tried to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial. It was a non-comparative, multicohort, single arm, open-label study of nivolumab in cHL (NCT02181738).
The study investigators found that 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 NK cells and a newly identified CD3−CD68+CD4+GrB+ subset.
The authors concluded that their results highlight the roles of recently expanded, clonally diverse CD4+ T cells and innate effectors in the efficacy of PD-1 blockade in cHL.
This work was supported in part by Bloodwise Fellowship, Helen Gurley Brown Fellowship, the US National Institutes of Health grants, the Miller Family Fund and the BMS International Immuno-Oncology Network.
Reference
Cader FZ, Hu X, Goh WL, et al. A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma. Nat Med; Published online 10 August 2020. DOI: https://doi.org/10.1038/s41591-020-1006-1