Targeting Tumors with IL-21 Reshapes the Tumor Microenvironment by Proliferating PD-1intTim-3-CD8+ T Cells.

The lack of sufficient functional tumor-infiltrating lymphocytes in the tumor microenvironment (TME) is one of the primary indications for the poor prognosis of patients with cancer. In this study, we developed an Erbitux- based IL-21 tumor-targeting fusion protein (Erb-IL21) to prolong the half-life and improve the antitumor efficacy of IL-21. Compared with Erb-IL2, Erb-IL21 demonstrated much lower toxicity in vivo. Mechanistically, Erb-IL21 selectively expanded functional cytotoxic T lymphocytes but not dysfunctional CD8(+)T cells in the TME. We observed that the IL-21-mediated antitumor effect largely depended on the existing i ntratu mora COB+T cells, instead of newly migrated CD8(+)T cells. Furthermore, Erb-IL-21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL-21 can target IL-21 to tumors and maximize the antitumor potential of checkpoint blockade by expending a subset of tumor antigen-specific CD8(+)T cells to achieve effective tumor control.