Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells
Sisi Deng, Zhichen Sun, Jian Qiao, Yong Liang, Longchao Liu, Chunbo Dong, Aijun Shen, Yang Wang, Hong Tang, Yang-Xin Fu, Hua Peng
Sisi Deng, Zhichen Sun, Jian Qiao, Yong Liang, Longchao Liu, Chunbo Dong, Aijun Shen, Yang Wang, Hong Tang, Yang-Xin Fu, Hua Peng
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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

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Figure 4

The antitumor effect of Erb-IL21 relies on preexisting intratumoral CD8+ CTLs and can generate a memory response.

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The antitumor effect of Erb-IL21 relies on preexisting intratumoral CD8+...
(A) Mice (n = 5–6) were inoculated with 2.5 × 105 MC38-cEGFR cells and were i.p. treated with 75 μg hIgG, anti-EGFR, or Erb-IL21 on days 10, 13, and 16. Mice were i.p. treated with 25 μg FTY720 1 day before treatment and every other day after treatment 5 times, and anti-CD8 antibody was i.p. injected 200 μg on days 9, 12, 15 and 18. (B) Approximately 30 days after tumor rejection by Erb-IL21 treatment, the tumor-free mice (n = 5) were inoculated with 2.5 × 106 MC38-cEGFR cells for the tumor-rechallenge assay. Naive WT C57BL/6 mice (n = 5) were used as control. (C) Approximately 30 days after tumor rejection in Erb-IL21–treated EGFR-Tg mice (n = 5), the tumor-free mice were injected with 2.5 × 106 MC38-cEGFR cells for the tumor-rechallenging assay. Naive EGFR-Tg mice were used as control. (D) Total drain lymph node cells from MC38-cEGFR tumor-bearing mice (n = 5–6) were stimulated with repeated freezing-thawing MC38-cEGFR or B16 tumor cells for 48 hours after control or Erb-IL21 treatment on day 20. IFN-γ–producing cells were enumerated by ELISPOT assay. Results are expressed as the number of spots/5 × 105 splenocytes. (E and F) C57BL/6 mice (n = 4–5) were inoculated with 1.5 × 105 MC38-cEGFR cells on the right flank of mice as in situ tumors and 0.5 × 105 MC38 cells on the left flank as distal tumors. They were intratumorally treated with 20 μg hIgG, Erbitux, and Erb-IL21 in MC38-cEGFR tumors on days 7, 9, 11, and 13. Tumor growth was measured and compared twice weekly. 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, ****P < 0.0001. One of two representative experiments is shown.