通过 IL-7 细胞因子疗法恢复 CD8 T 细胞动态，从而使免疫检查点阻断在 T 淋巴细胞减少症中发挥疗效

To investigate ICB responsiveness depending on the severity of TLP, first, we established TLP mouse models that mimic clinically observed mild and severe TLP through thymectomy and anti-Thy1-induced peripheral T cell depletion. T cell-replete mice and T-lymphopenic mice were inoculated with palpable or advanced tumors to evaluate the antitumor efficacy of anti-PD-1 therapy according to the severity of TLP. Additionally, by utilizing established murine models, we analyzed matched blood, tumor-draining lymph nodes (TDLNs), and tumor samples by flow cytometry to investigate the mechanisms by which ICB responsiveness is impaired under T-lymphopenic conditions. Finally, to evaluate the combination effect of anti-PD-1 and recombinant IL-7 cytokine therapy (rhIL-7-hyFc) in T-lymphopenic conditions, we administered anti-PD-1, rhIL-7-hyFc, or both to advanced tumor-bearing T-lymphopenic mice and subsequently analyzed tumor growth and survival rates.

Using mouse models mimicking clinical TLP, we observed that the antitumor efficacy of anti-PD-1 therapy was severely impaired in TLP, depending on the degree of TLP and the immunogenicity of the tumors. TLP mice showed a significant reduction in systemic CD8 T cells but stable intratumoral CD8 T cell numbers, suggesting maintained tumor infiltration despite systemic downregulation. Crucially, TLP led to a shift in the composition of tumor-infiltrating lymphocytes, with a decrease in PD-1 + tumor-reactive CD8 T cells and an increase in PD-1 - bystander cells. This reduction in PD-1 + cells was linked to impaired clonal expansion in tumor-draining lymph nodes. To counteract these effects, we introduced recombinant IL-7 cytokine therapy (rhIL-7-hyFc), which effectively restored systemic T cell counts, enhanced PD-1 + CD8 T cell proliferation within tumors, and increased the population of stem-like progenitor cells. The combination of rhIL-7-hyFc and anti-PD-1 therapy resulted in significant tumor regression and improved mouse survival. DISCUSSION: Our findings highlight the critical role of IL-7 in reshaping the CD8 T cell landscape to improve ICB efficacy in TLP conditions, proposing a sequential therapeutic approach: conventional therapy to reduce tumor burden and enhance immunogenicity, followed by IL-7 therapy to restore and rejuvenate CD8 T cells, culminating in effective ICB treatment.