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A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8⁺ T-cell response and effective tumor control.

ABSTRACT: While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.

SUBMITTER: Sun Z

PROVIDER: S-EPMC6713724 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8<sup>+</sup> T-cell response and effective tumor control.

Sun Zhichen Z Ren Zhenhua Z Yang Kaiting K Liu Zhida Z Cao Shuaishuai S Deng Sisi S Xu Lily L Liang Yong Y Guo Jingya J Bian Yingjie Y Xu Hairong H Shi Jiyun J Wang Fan F Fu Yang-Xin YX Peng Hua H

Nature communications 20190828 1

While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and spe ...[more]

PMID: 31462678

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Project description:BackgroundStratification of patients who could benefit from immune checkpoint inhibitor (ICI) therapy is of much importance. PD-1hiCD8+ T cells represent a newly identified and effective biomarker for ICI therapy response biomarker in lung cancer. Accurately quantifying these T cells using commonly available RNA sequencing (RNA-seq) data may extend their applications to more cancer types.MethodWe built a transcriptome signature of PD-1hiCD8+ T cells from bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data of tumor-infiltrating immune cells. The signature was validated by flow cytometry and in independent datasets. The clinical applications of the signature were explored in non-small-cell lung cancer, melanoma, gastric cancer, urothelial cancer, and a mouse model of breast cancer samples treated with ICI, and systematically evaluated across 21 cancer types in The Cancer Genome Atlas (TCGA). Its associations with other biomarkers were also determined.ResultsSignature scores could be used to identify the PD-1hiCD8+ T subset and were correlated with the fraction of PD-1hiCD8+ T cells in tumor tissue (Pearson correlation, R=0.76, p=0.0004). Furthermore, in the scRNA-seq dataset, we confirmed the capability of PD-1hiCD8+ T cells to secrete CXCL13, as well as their interactions with other immune cells. In 581 clinical samples and 204 mouse models treated with ICIs, high signature scores were associated with increased survival, and the signature achieved area under the receiver operating characteristic curve scores of 0.755 (ranging from 0.61 to 0.91) in predicting therapy response. In TCGA pan-cancer datasets, our signature scores were consistently correlated with therapy response (R=0.78, p<0.0001) and partially explained the diverse response rates among different cancer types. Finally, our signature generally outperformed other mRNA-based predictors and showed improved predictive performance when used in combination with tumor mutational burden (TMB). The signature score is available in the R package "PD1highCD8Tscore" (https://github.com/Liulab/PD1highCD8Tscore).ConclusionThrough estimating the fraction of the PD-1hiCD8+ T cell, our signature could predict response to ICI therapy across multiple cancers and could serve as a complementary biomarker to TMB.

Dataset Information

A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8⁺ T-cell response and effective tumor control.

Publications

A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8<sup>+</sup> T-cell response and effective tumor control.

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Dataset Information

A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control.

Publications

A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8<sup>+</sup> T-cell response and effective tumor control.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8⁺ T-cell response and effective tumor control.