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Dual Activation of CD8+ and CD4+ T cells by a PD-1 targeted IL-15 Mutein in Viral Infection

ABSTRACT: Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses, in part due to insufficient T cell reinvigoration. Cytokines remain promising additions to immunotherapy to improve response rates; however, the low therapeutic index and associated side effects have hindered progress. In response to these challenges, immunocytokines, engineered fusion proteins that combine the specificity of antibodies with the immune-stimulatory properties of cytokines, have been employed to enable targeted delivery of cytokine signals to immune cells or the tumor microenvironment to minimize pathological consequences. Here, we describe SAR445877 (SAR’877), a novel PD-1-targeted immunocytokine that fuses a high-affinity anti-PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR’877 simultaneously blocks PD-1/PD-L1 and PD-1/PD-L2 interactions and delivers IL-15 signals selectively to PD-1+ T cells. This design enhances the proliferation and activation of antigen-experienced CD8⁺ and CD4⁺ T cells, as well as NK cells, while limiting systemic inflammatory cytokine release. Mechanistically, SAR’877 preferentially activates STAT5 signaling in PD-1⁺ lymphocytes and restores effector function in exhausted T cells in vitro. A murine surrogate of SAR’877 accelerated viral clearance and reinvigorated exhausted T cells in the chronic LCMV Clone-13 infection model. In multiple syngeneic tumor models, the surrogate induced robust anti-tumor immunity by expanding cytotoxic CD8⁺ T cells and promoting Th1 polarization. Notably, SAR’877 outperformed combination therapy with anti-PD-1 and untargeted IL-15, underscoring the therapeutic potential of targeted IL-15 delivery to PD-1+ cells. These findings position SAR’877 as a promising next-generation checkpoint immunotherapy that augments efficacy while reducing cytokine-associated toxicities.

ORGANISM(S): Mus musculus

PROVIDER: GSE323389 | GEO | 2026/04/21

REPOSITORIES: GEO

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Project description:In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed upregulation of ribosome-related genes and downregulation of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.

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Dual Activation of CD8+ and CD4+ T cells by a PD-1 targeted IL-15 Mutein in Viral Infection

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