CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer

Yi Li; Hui Zhang; Qin Li; Pingjin Zou; Xingxiang Huang; Chihua Wu; Li Tan

doi:10.1016/j.canlet.2020.09.011

CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer

Cancer Lett. 2020 Dec 28:495:12-21. doi: 10.1016/j.canlet.2020.09.011. Epub 2020 Sep 15.

Authors

Yi Li¹, Hui Zhang², Qin Li³, Pingjin Zou³, Xingxiang Huang³, Chihua Wu⁴, Li Tan⁵

Affiliations

¹ Department of Breast Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
² Department of Ultrasound, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
³ School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China.
⁴ Department of Breast Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China. Electronic address: wuchihua@med.uestc.edu.cn.
⁵ Department of Ultrasound, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China. Electronic address: tanlics@med.uestc.edu.cn.

PMID: 32941949
DOI: 10.1016/j.canlet.2020.09.011

Abstract

Immunogenic cell death (ICD) improves the T cell response against different tumors, indicating that ICD can enhance the antitumor immunity elicited by the anti-checkpoint antibody anti-programmed death 1 (anti-PD-1). In the present study, we reported a synergistic and durable immune-mediated antitumor response elicited by the combined treatment of SR-4835, a CDK12/13 specific inhibitor, with PD-1 blockade in a syngeneic mouse model. The developed combination therapy elicited antitumor activity in immunocompetent mouse tumor models. Furthermore, the SR-4835-treated tumor cells exhibited characteristics of ICD, including the release of high mobility group box 1 (HMGB1) and ATP and calreticulin (CRT) translocation. This activity led to a signiﬁcant T-cell-dependent tumor suppression. The enhanced dendritic cell (DC) and infiltration of T cells activation in the tumors treated with both SR-4835 and anti-PD-1 indicate that this combination treatment promotes an improved immune response. Therefore, the results of the present study demonstrate the potential of CDK12/13 inhibition combined with checkpoint inhibition in breast cancer treatment.

Keywords: CDK12/13; Immunogenic cell death; Immunotherapy; PD-1; SR-4835.

Publication types

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

MeSH terms

Animals
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
CDC2 Protein Kinase / antagonists & inhibitors*
Calreticulin / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cyclin-Dependent Kinases / antagonists & inhibitors*
Drug Synergism
Female
Gene Expression Regulation, Neoplastic / drug effects
HMGB1 Protein / metabolism
Humans
Immune Checkpoint Inhibitors / administration & dosage*
Immune Checkpoint Inhibitors / pharmacology
Immunogenic Cell Death
MCF-7 Cells
Mice
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
Protein Kinase Inhibitors / administration & dosage*
Protein Kinase Inhibitors / pharmacology
Protein Transport
Xenograft Model Antitumor Assays

Substances

CALR protein, human
Calreticulin
HMGB1 Protein
HMGB1 protein, human
Immune Checkpoint Inhibitors
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Protein Kinase Inhibitors
CDC2 Protein Kinase
CDK12 protein, human
CDK13 protein, human
Cyclin-Dependent Kinases