Long-acting IL-7 induces distinct transcriptomic features in peripheral T cells of patients with solid tumors
Hocheol Jang, Jeong Yeon Kim, Sojeong Kim, Heewon Kim, Mi Sun Byun, Myung Ah Lee, Jong Hee Chang, Do-Hyun Nam, Tae Won Kim, Sin-Soo Jeun, Joo Hyuk Sohn, Su-Hyung Park, Eui-Cheol Shin
Hocheol Jang, Jeong Yeon Kim, Sojeong Kim, Heewon Kim, Mi Sun Byun, Myung Ah Lee, Jong Hee Chang, Do-Hyun Nam, Tae Won Kim, Sin-Soo Jeun, Joo Hyuk Sohn, Su-Hyung Park, Eui-Cheol Shin
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Clinical Research and Public Health Clinical Research Immunology Oncology

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.FUNDING National Research Foundation of Korea (NRF-2022R1A2C3007292 and RS-2024-00439160), Ministry of Food and Drug Safety (RS-2025-02213409), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (RS-2025-25460003).

Authors

Hocheol Jang, Jeong Yeon Kim, Sojeong Kim, Heewon Kim, Mi Sun Byun, Myung Ah Lee, Jong Hee Chang, Do-Hyun Nam, Tae Won Kim, Sin-Soo Jeun, Joo Hyuk Sohn, Su-Hyung Park, Eui-Cheol Shin

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Figure 1

Study design.

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Study design. (A) Schematic overview of sample collection. PBMCs were co...
(A) Schematic overview of sample collection. PBMCs were collected from patients with colorectal cancer (CRC; n = 4) and glioblastoma (GBM; n = 3) before and after rhIL-7-hyFc administration. CRC patients received 2 doses. (B) Schematic illustration of the single-cell sequencing workflow. To assess the effects of rhIL-7-hyFc on peripheral T cells, sorted T cells were subjected to scRNA-seq and scTCR-seq. (C) Cell-type annotation of single cells. A total of 185,331 cells were first annotated as CD4+ or CD8+ T cells, and then further classified using canonical gene markers. (D) Expression of canonical markers in T cells. The expressions of well-established genes associated with a naive state, survival, memory, activation, cytotoxicity, inhibition, and proliferation were plotted to characterize each cluster. (E) Proportions of the CD8+ T cell (left) and CD4+ T cell (right) subsets per patient at baseline (W0) and 1 week after treatment (W1). (F and G) Proportion of proliferating CD8 (F) and CD4 (G) cluster per sample, based on scRNA-seq data from W0 and W1 (n = 7). Paired t test was used for comparison. **P < 0.01, ****P < 0.0001.