IL-27 gene therapy induces depletion of Tregs and enhances the efficacy of cancer immunotherapy.

Tumor-induced expansion of Tregs is a significant obstacle to cancer immunotherapy. However, traditional approaches to deplete Tregs are often inefficient, provoking autoimmunity. We show here that administration of IL-27-expressing recombinant adeno-associated virus (AAV-IL-27) significantly inhibits tumor growth and enhances T cell responses in tumors. Strikingly, we found that AAV-IL-27 treatment causes rapid depletion of Tregs in peripheral blood, lymphoid organs, and - most pronouncedly - tumor microenvironment. AAV-IL-27-mediated Treg depletion is dependent on IL-27 receptor and Stat1 in Tregs and is a combined result of CD25 downregulation in Tregs and inhibition of IL-2 production by T cells. In combination with a GM-CSF vaccine, AAV-IL-27 treatment not only induced nearly complete tumor rejection, but also resulted in amplified neoantigen-specific T cell responses. AAV-IL-27 also dramatically increased the efficacy of anti-PD-1 therapy, presumably due to induction of PD-L1 in T cells and depletion of Tregs. Importantly, AAV-IL-27 therapy did not induce significant adverse events, partially due to its induction of IL-10. In a plasmacytoma mouse model, we found that IL-10 was required for AAV-IL-27-mediated tumor rejection. Thus, our study demonstrates the potential of AAV-IL-27 as an independent cancer therapeutic and as an efficient adjuvant for cancer immunotherapy.