hetIL-15 therapy results in tumor control by promoting tumor infiltration of CD8+ T cells with increased cytotoxic potential and decreased PD-1 expression.

Interleukin-15 (IL-15) is a common γ-chain cytokine that plays a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha chain that are together termed heterodimeric IL-15 (hetIL-15). We investigated the anti-tumor efficacy of hetIL-15 in several mouse cancer models. Repeated injections of hetIL-15 were effective in delaying tumor growth in the MC38 colon carcinoma and the B16 melanoma models. The beneficial effects of hetIL-15 therapy included a significantly reduced onset of lung metastasis in 4T1 breast cancer-bearing mice. We study the mechanisms of antitumor effects of hetIL-15 in several tumor models. hetIL-15 administration promoted a dramatic increase of tumor infiltration and persistence of CD8 + T cells, including tumor specific T cells, and resulted in an increased CD8 + /Treg ratio. Tumor-resident CD8 + T cells showed features of effectors cells and were characterized by increased proliferation (Ki67 + ) and high cytotoxic potential (Granzyme B + ). In the absence of hetIL-15, the smaller population of tumor-infiltrating T cells exhibited high levels of the exhaustion marker PD-1, potentially limiting their anti-cancer effectiveness. Provision of hetIL-15 resulted in a significant decrease in lymphocyte expression of PD-1, alleviating one potential mechanism for the exhaustion phenotype. Preclinical cancer studies support the use of hetIL-15 in tumor immunotherapy approaches to promote the development of anti-tumor responses by favoring effector over regulatory cells.