Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds

Haiyan Wang; Shasha Li; Qianyu Wang; Zhengshuo Jin; Wei Shao; Yan Gao; Lu Li; Kequan Lin; Lin Zhu; Huili Wang; Xuebin Liao; Dong Wang

doi:10.1126/sciadv.abd7851

Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds

Sci Adv. 2021 Jan 22;7(4):eabd7851. doi: 10.1126/sciadv.abd7851. Print 2021 Jan.

Authors

Haiyan Wang^{1

2}, Shasha Li², Qianyu Wang³, Zhengshuo Jin², Wei Shao², Yan Gao⁴, Lu Li³, Kequan Lin³, Lin Zhu³, Huili Wang², Xuebin Liao⁴, Dong Wang^{5

6

7

8}

Affiliations

¹ Department of Pathology, School of Medicine, Qinghai University, Xining 810001, China.
² Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
³ School of Life Sciences, Tsinghua University, Beijing 100084, China.
⁴ School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
⁵ Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. dwang@cdutcm.edu.cn.
⁶ Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
⁷ Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China.
⁸ State Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.

Abstract

Combination immunotherapy is promising to overcome the limited objective response rates of immune checkpoint blockade (ICB) therapy. Here, a tumor immunological phenotype (TIP) gene signature and high-throughput sequencing-based high-throughput screening (HTS²) were combined to identify combination immunotherapy compounds. We firstly defined a TIP gene signature distinguishing "cold" tumors from "hot" tumors. After screening thousands of compounds, we identified that aurora kinase inhibitors (AKIs) could reprogram the expression pattern of TIP genes in triple-negative breast cancer (TNBC) cells. AKIs treatments up-regulate expression of chemokine genes CXCL10 and CXCL11 through inhibiting aurora kinase A (AURKA)-signal transducer and activator of transcription 3 (STAT3) signaling pathway, which promotes effective T cells infiltrating into tumor microenvironment and improves anti-programmed cell death 1 (PD-1) efficacy in preclinical models. Our study established a novel strategy to discover combination immunotherapy compounds and suggested the therapeutic potential of combining AKIs with ICB for the treatment of TNBC.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, Non-U.S. Gov't