Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells
Sisi Deng, … , Yang-Xin Fu, Hua Peng
Sisi Deng, … , Yang-Xin Fu, Hua Peng
Published April 9, 2020
Citation Information: JCI Insight. 2020;5(7):e132000. https://doi.org/10.1172/jci.insight.132000.
View: Text | PDF
Research Article Immunology Oncology

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

Abstract

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 intratumoral CD8+ T cells, instead of newly migrated CD8+ T cells. Furthermore, Erb-IL21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL21 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.

Authors

Sisi Deng, Zhichen Sun, Jian Qiao, Yong Liang, Longchao Liu, Chunbo Dong, Aijun Shen, Yang Wang, Hong Tang, Yang-Xin Fu, Hua Peng

×

Figure 1

Local delivery of IL-21 is superior to systemic delivery for tumor control.

Options: View larger image (or click on image) Download as PowerPoint
Local delivery of IL-21 is superior to systemic delivery for tumor contr...
(A) WT C57BL/6 mice (n = 4–5) were injected subcutaneously (s.c.) with 5 × 105 MC38 cells and intratumorally (i.t.) or i.p. treated with 5 μg hIgG or IL21-Fc on days 9, 12, and 15. (B) Schematic structure of fusion proteins of LA22-IL21 and Erb-Il21. (C and D) C57BL/6 mice (n = 6) were inoculated with 2.5 × 105 MC38-cEGFR cells in the right flank and 5 × 105 MC38 in the left flank on day 0 and then i.v. treated with 75 μg Cy5.5-labeled Erb-IL21 or 75 μg Cy5.5-labeled LA22-IL21 on day 8. Mice without treatment served as a control. Six hours after treatment, the relative fluorescence intensity of MC38-cEGFR tumor subtracted by that of MC38 tumor after treatment is shown. (E) Tumor-bearing C57BL/6 mice (n = 6) were inoculated with 2.5 × 105 MC38-cEGFR cells on day 0 and then i.p. treated with 40 μg hIgG, 40 μg Erbitux, 16 μg IL21-FC, 40 μg LA22-IL21, or 40 μg Erb-IL21 on days 11, 14, and 17. (F) EGFR-Tg mice (n = 6) were inoculated with 2.5 × 105 MC38-cEGFR cells and i.p. treated with 75 μg hIgG, Erbitux or Erb-IL21 on days 10, 13, and 16. Tumor growth was measured and compared every week. The mean ± SEM values are shown. Two-way ANOVA tests were used to analyze the tumor growth data, and unpaired t tests were used to analyze the other data. *P < 0.05, **P < 0.01, ****P < 0.0001. One of two representative experiments is shown.