Abstract
Focal radiotherapy can promote cross-presentation of tumor antigens to T cells, but by itself, it is insufficient to induce therapeutically effective T-cell responses. The common gamma-chain cytokine IL15 promotes and sustains the proliferation and effector function of CD8+ T cells but has limited activity against poorly immunogenic tumors that do not elicit significant spontaneous T-cell responses. Here, we show that radiotherapy and subcutaneous IL15 had complementary effects and induced CD8+ T-cell-mediated tumor regression and long-term protective memory responses in two mouse carcinoma models unresponsive to IL15 alone. Mechanistically, radiotherapy-induced IFN type I production and Batf3-dependent conventional dendritic cells type 1 (cDC1) were required for priming of tumor-specific CD8+ T cells and for the therapeutic effect of the combination. IL15 cooperated with radiotherapy to activate and recruit cDC1s to the tumor. IL15 alone and in complex with a hybrid molecule containing the IL15α receptor have been tested in early-phase clinical trials in patients with cancer and demonstrated good tolerability, especially when given subcutaneously. Expansion of natural killer (NK) cells and CD8+ T cells was noted, without clear clinical activity, suggesting further testing of IL15 as a component of a combinatorial treatment with other agents. Our results provide the rationale for testing combinations of IL15 with radiotherapy in the clinic.