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TGF-βRII/IL-15 Immunotherapeutic complex targets exhausted CD8+ T cell subsets in lymph nodes and tumors

ABSTRACT: Exhausted CD8+ T cells, located within the tumor-draining lymph nodes (TDLNs) are responsible for maintaining tumor-specific responses in cancer. Here, we demonstrate that a bifunctional TGF-βRII/IL-15 protein complex (HCW9218), with TGF-β neutralization and IL-15 immunostimulatory activities, is capable of localizing to the TDLNs and tumors after subcutaneous administration, neutralizes TGF-β, expands progenitor stem-like exhausted T cells (TPEX) in TDLNs, and promotes their infiltration into tumors. Immune-checkpoint-inhibitors (ICIs) significantly enhanced the effects of HCW9218 on TPEX, and synergistically improved HCW9218 anti-tumor efficacy in melanoma and reduced spontaneous lung metastasis in breast cancer models. In a dose-escalating clinical trial in patients with chemo-refractory/relapsed solid tumors, HCW9218 monotherapy was well-tolerated, reduced serum TGF-β levels, promoted CD8+ T cell expansion in peripheral blood and CD8+ T cell infiltration in tumor biopsies. These findings provide a strong basis for using HCW9218 to enhance the efficacy of ICIs against solid tumors in the clinical setting.

ORGANISM(S): Mus musculus

PROVIDER: GSE301523 | GEO | 2025/07/07

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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TGF-βRII/IL-15 Immunotherapeutic complex targets exhausted CD8+ T cell subsets in lymph nodes and tumors

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