Long-acting IL-7 induces distinct transcriptomic features in peripheral T cells of patients with solid tumors

Abstract

BACKGROUND. IL-7 is a critical cytokine in T cell development, survival, and homeostasis. Previous preclinical and clinical studies reported that IL-7 treatment increased T cell counts, but its effect on peripheral blood T cells in cancer patients and molecular mechanisms have not been explored. METHODS. We investigated effects of long-acting recombinant human IL-7 conjugated to a hybrid IgD/IgG4 Fc domain (rhIL-7-hyFc) on peripheral T cells in patients with advanced solid tumors. Peripheral blood samples were collected before and after treatment, followed by analysis through single-cell transcriptomics and flow cytometry. RESULTS. We found that rhIL-7-hyFc induced marked expansion of proliferating T cells, and promoted transcriptional changes associated with immune activation, cell cycle progression, and antiapoptosis. Trajectory analysis revealed that posttreatment T cells had distinct transcriptional states enriched for cytokine-and TCR-mediated signaling pathways. Notably, a second dose administered after 3 weeks yielded diminished proliferation and minimal transcriptional changes, which were independent of antidrug antibody or CD127 downmodulation. Examination of elements of the IL-7 signaling pathway revealed intact proximal signaling (e.g., STAT5 phosphorylation) but downregulation of distal elements, including PIM-1 kinase and c-Myc. CONCLUSIONS. Our results demonstrate that rhIL-7-hyFc induces robust peripheral T cell expansion and activation in patients with solid tumors, supporting its potential use for lymphopenic patients treated with cancer immunotherapy. TRIAL REGISTRATION. ClinicalTrials.gov NCT03478995 and NCT03619239.