IL-7 producing immunotherapy improves ex vivo T cell functions of immunosenescent patients, especially post hip fracture

Abstract

Following acute stress such as trauma or sepsis, most of critically ill elderly patients become immunosuppressed and susceptible to secondary infections and enhanced mortality. We have developed a virus-based immunotherapy encoding human interleukin-7 (hIL-7) aiming at restoring both innate an adaptative immune homeostasis in these patients. We assessed the impact of this encoded hIL-7 on the ex vivo immune functions of T cells from PBMC of immunosenescent patients with or without hip fracture. T-cell ex vivo phenotyping was characterized in terms of senescence (CD57), IL-7 receptor (CD127) expression, and T cell differentiation profile. Then, post stimulation, activation status, and functionality (STAT5/STAT1 phosphorylation and T cell proliferation assays) were evaluated by flow cytometry. Our data show that T cells from both groups display immunosenescence features, express CD127 and are activated after stimulation by virotherapy-produced hIL-7-Fc. Interestingly, hip fracture patients exhibit a unique functional ability: An important T cell proliferation occurred compared to controls following stimulation with hIL-7-Fc. In addition, stimulation led to an increased naïve T cell as well as a decreased effector memory T cell proportions compared to controls. This preliminary study indicates that the produced hIL-7-Fc is well recognized by T cells and initiates IL-7 signaling through STAT5 and STAT1 phosphorylation. This signaling efficiently leads to T cell proliferation and activation and enables a T cell “rejuvenation.” These results are in favor of the clinical development of the hIL-7-Fc expressing virotherapy to restore or induce immune T cell responses in immunosenescent hip fracture patients.

Single-cell landscape of immunological responses in elderly patients with sepsis

“…Remarkably, previous studies have shown that IL-7 administration can reverse sepsis-induced lymphopenia by inhibiting apoptosis and improving the proliferation of T lymphocytes, which was recently demonstrated in a clinical trial [ 29 , 30 ]. In addition, IL-7 increases the activation and promotes the rejuvenation of T cells in patients with immunosenescence, as reported by Marton et al [ 31 ]. Considering both aggravated immune cell apoptosis and profound immune exhaustion in elderly patients, with sepsis, IL-7 may be an underlying immunotherapeutic strategy, and its efficacy is highly anticipated.…”