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T Cell Receptor Repertoire Linked to Anti-PD-1 Therapy Response in Hodgkin Lymphoma

NEW YORK – Researchers at the Dana-Farber Cancer Institute, Harvard Medical School, and elsewhere have discovered a peripheral immune signature that is associated with responsiveness to anti-PD-1 therapy in Hodgkin lymphoma patients.

In a paper published on Monday in Nature Medicine, the researchers noted that PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs) that exhibit frequent copy-number gains of CD274 (PD-L1) and PDC1LG2 (PD-L2) on chromosome 9p24.1, but that the mechanism of action of anti-PD-1 therapy remains undefined. In their study, the investigators used T cell receptor (TCR) sequencing and cytometry by time-of-flight (CyTOF) analysis to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated with nivolumab (Bristol-Myers Squibb's Opdivo) in the CheckMate 205 phase II clinical trial.

They 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. They also noted that CD4+ TCR diversity significantly increased during therapy, most prominently in patients who had achieved complete responses, but did not make the same observation for CD8+ TCR diversity. Further, the researchers said, patients who responded to therapy had an increased abundance of activated natural killer (NK) cells and a newly identified subset of CD3- CD68+ CD4+ GrB+ cells.

Initially, the researchers noted that baseline TCR diversity was significantly higher in healthy donors than in patients with newly diagnosed cHL, indicating that these patients had a reduced TCR repertoire prior to the initiation of therapy. Additionally, TCR diversity was significantly higher in patients with newly diagnosed cHL than in patients with relapsed or refractory disease, potentially reflecting disease progression or prior treatment.

Baseline TCR diversity in patients with relapsed or refractory disease who achieved a complete response with nivolumab was not significantly different from that in newly diagnosed patients, the researchers found. In contrast, it was significantly lower in patients with relapsed or refractory disease who obtained only a partial response or had progressive disease following PD-1 blockade. These findings prompted the investigators to perform TCR sequencing of highly purified peripheral CD4+ and CD8+ T cells and assess their respective repertoires in healthy donors, patients with newly diagnosed cHL, and trial patients with relapsed or refractory cHL who were treated with nivolumab beginning one year or more after autologous stem cell transplantation (ASCT) at baseline and following PD-1 blockade.

They found that the trial patients had no significant differences in ratios of input CD4+ and CD8+ T cells or total detected CD4+ and CD8+ TCR sequences at baseline, but that peripheral CD4+ TCR repertoire diversity was significantly higher in healthy donors than in patients with newly diagnosed or relapsed or refractory cHL. While baseline CD4+ TCR diversity was not significantly different in newly diagnosed patients and those with relapsed or refractory disease who had complete responses to nivolumab, it was significantly lower in patients with partial responses or progressive disease. They saw similar patterns in baseline CD8+ TCR diversity.

After characterizing baseline differences in CD4+ and CD8+ TCR diversity in trial patients, the researchers assessed dynamic changes in these repertoires following PD-1 blockade. After six weeks of therapy, there was a highly significant increase in CD4+, but not CD8+, TCR repertoire diversity. Further, the selective increase in CD4+ TCR repertoire diversity was most apparent in patients who achieved complete responses to nivolumab.

Given the association between increased TCR repertoire diversity and response to PD-1 blockade, the investigators went on to evaluate clonal T cell expansion following therapy. In patients who were treated with nivolumab one year or more after ASCT, they identified more than 4 million unique TCR sequences at baseline, nearly 800,000 of which expanded by at least twofold following treatment. When comparing the expansion of T cell clones derived from singletons or non-singletons and assessing the ratio of expanded singleton over non-singleton T cells following PD-1 blockade, the researchers found that patients who achieved a complete response exhibited significantly greater expansion of singleton over non-singleton clones, in comparison with those who obtained only a partial response or progressive disease.

The investigators further identified an additional circulating CD3- CD68+ CD4+ GrB+ subset that was associated with response to PD-1 blockade and detectable in the tumor microenvironment of relapsed cHLs. Importantly, they added, cHL patients with the most favorable responses to PD-1 blockade had coordinate CD3- peripheral immune signatures consisting of increased circulating B cells, NK cells, and CD68+GrB+ innate cells that were more like those of healthy donors.

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