IL15/IL15Rα Complex Induces an Antitumor Immune Response following Radiotherapy only in the Absence of Tregs and Fails to Expand Progenitor TCF1+ CD8 T Cells.

In this work, we show that the combination of radiotherapy (RT) and an IL15/IL15Rα fusion complex (IL15c) fails to confer antitumor efficacy; however, a CD8-driven antitumor immune response can be elicited with the concurrent administration of an aCD25 regulatory T cell-depleting antibody. Using IL15-/- and Rag1-/- knockout mouse models, we show that the response to RT + IL15c + aCD25 is dependent on both IL15 and cytotoxic T lymphocytes. Furthermore, despite an equivalent survival benefit following treatment with RT + IL15c + aCD25 and combination RT and PD1-IL2v, a novel immunocytokine with PD1- and IL2Rβγ-binding domains, cytotoxic T lymphocyte immunophenotyping and phosphoproteomics analysis of intracellular metabolites showed a significant upregulation of activation and functionality in CD8 T cells in the RT + PD1-IL2v regimen. Finally, we show that in the absence of functional IL15 signaling, the immunostimulatory response to RT + PD1-IL2v is significantly diminished with a concurrent lack of TCF+ CD8 T-cell generation, suggesting a necessity of IL15 for CD8 stem cells in mediating a durable response to treatment. Together, our results are illustrative of a mechanism wherein unimpeded effector T-cell activation through IL2Rβ signaling and regulatory T-cell inhibition are necessary in mediating an antitumor immune response.