Effect of IL-7 therapy on virus-specific CD8 T cell response during chronic viral infection [multiomic]

PD-1+TCF-1+ stem-like CD8 T cells, also referred to as progenitors of exhausted T cells (TPEX), are a crucial resource pool for maintaining CD8 T cell during chronic viral infections and cancer. These stem-like CD8 T cells are a key therapeutic target in antiviral and anticancer immunotherapy as they provide a proliferative burst of effector CD8 T cells upon PD-1 blockade therapy. In our study we show that IL-7 therapy preferentially expands these stem-like CD8 T cells, using NT-I7, a long-acting hybrid Fc-fused recombinant human IL-7 (rhIL-7-hyFc, efineptakin alfa). Single-cell gene profile analysis revealed a proliferating cluster induced by NT-I7, distinct from previously described stem-like, transitory effector, or terminally exhausted subset cluster. This cluster exhibited an enriched stem-like signature, including transcription factors and costimulatory molecules associated with stem-like CD8 T cells. Notably, the cluster was enriched with genes related to lymphocyte migration. Consistent with this gene profile, there was a significant increase in stem-like CD8 T cells in circulation and peripheral tissues after NT-I7 treatment, contrasting with their resident property in lymphoid organs. Our data suggest the potential of NT-I7 therapy to enhance antiviral and anticancer immunotherapies by amplifying the stem-like CD8 T cell pool and mobilizing them to the peripheral target sites. Overall design: C57Bl/6J mice were intravenously infected with 2x10^6 LCMV clone-13 with transient CD4 depletion. >45 days post infection, mice were treated with a single dose of injection buffer or NT-I7, a hybrid Fc-fused recombinant human IL-7 (hIL-7-hyFc, efineptakin alfa). 8 or 14 days after the injection, LCMV-GP33 Tet+ CD8 T cells from the spleen were sorted for single cell RNA sequencing.