Effects of exogenous interleukin-7 on T cells in healthy adults and cancer patients

Abstract

Interleukin-7 (IL-7) is an essential cytokine involved in peripheral T-cell homeostasis. Clinical studies have indicated the potential of IL-7 as a therapeutic agent for various diseases involving lymphopenia. However, the mechanisms involved in the effects of exogenous administration of recombinant IL-7 remain unclear. Here, we investigated the effects on T lymphocytes of a single administration of hIL-7-hyFc to healthy adults, such as T-cell dynamics, cellular response kinetics, and qualitative changes. The CD8$^+$ and CD4$^+$ T-cell numbers transiently decreased up to 3 days after a single administration of hIL-7-hyFc, and subsequently increased with peak numbers achieved after day 21, reaching up to 2.5-fold and 2-fold, respectively. Among CD8$^+$ and CD4$^+$ T cells, all T-cell subsets (T$_N$, T$_{EM}$, T$_{CM}$, and T$_{EMRA}$) increased significantly. However, the regulatory T cells did not significantly increase. Cellular responses to exogenous IL-7 in CD8$^+$ and CD4$^+$ T cells were robust during the first week with upregulated expression of Ki-67 and BCL2 molecules, peaking at days 3 and 7, respectively. In addition, while T-cell receptor (TCR) repertoire diversity of memory CD8$^+$ and CD4$^+$ T cells was maintained, that of naïve subsets increased on day 56. Moreover, gene expression profiles related to T-cell function or in genes related to T-cell exhaustion, senescence, and anergy were not significantly altered after a robust increase in T cell numbers. Additionally, the effector functions of antigen-specific CD8$^+$ T cells were maintained after hIL-7-hyFc administration. Further, we explored the effects of administration of hIL-7-hyFc on anti-tumor immunity in patients with metastatic solid tumors or glioblastomas (GBM) experiencing chemotherapy-induced lymphopenia. In cancer patients, absolute lymphocyte counts (ALCs) were dramatically increased by a single administration of hIL-7-hyFc after week 3, whether patients had normal or low ALCs. Although severe lymphopenia recovered to the normal range, mild lymphopenia was fully recovered. Moreover, these ALC increases in patients with lymphopenia were durable over 12 weeks. In addition, hIL-7-hyFc increased the absolute numbers of all subsets of CD8$^+$ and CD4$^+$ T cells, but preferentially increased the TN subset in CD8$^+$ T cells. In circulation, naïve and fresh subsets of CD8$^+$ T cells increased, while TEMRA and senescent subsets decreased at week 3. Next, hIL-7-hyFc enhanced the expression of chemokine receptors on CD8$^+$ and CD4$^+$ T cells and increased recruitment of T cells into tumor and normal tissue adjacent to the tumor (NAT). Moreover, the total number of tumor-specific T cells with effector functions in circulation increased. The results of this study suggest that hIL-7-hyFc administration induced long-lasting augmentation of the numbers of CD8$^+$ and CD4$^+$ T cells, but not regulatory T cells, without qualitative changes. Additionally, the results suggest that hIL-7-hyFc administration restored lymphopenia in cancer patients, rejuvenated CD8$^+$ T cell populations, and enhanced anti-tumor immunity by increasing T cells at the tumor site and tumor-specific effector T cells in circulation. This supports the potential utility of hIL-7-hyFc as a therapeutic agent for patients with compromised T-cell immunity, cancer immunotherapy, and for elderly individuals as a vaccine adjuvant.