2. Academic Validation
  3. Shikonin improves the effectiveness of PD-1 blockade in colorectal cancer by enhancing immunogenicity via Hsp70 upregulation

Shikonin improves the effectiveness of PD-1 blockade in colorectal cancer by enhancing immunogenicity via Hsp70 upregulation

  • Mol Biol Rep. 2024 Jan 6;51(1):86. doi: 10.1007/s11033-023-09056-2.
Jinghua Chen 1 2,  Jie Liu 3,  Xiaolin Liu 2,  Jun Wang 2,  Xiumei Wang 4,  Xin Ye 2,  Qi Xie 5,  Jing Liang 6,  Yan Li 7 8
Affiliations

Affiliations

  • 1 Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
  • 2 Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Department of Oncology, Shandong Lung Cancer Institute, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.
  • 3 Department of Pediatric Intensive Care Unit, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China.
  • 4 Department of Oncology, The Yuncheng Chenxin Hospital, Heze, China.
  • 5 Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Department of Oncology, Shandong Lung Cancer Institute, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China. xieqi@sdfmu.edu.cn.
  • 6 Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Department of Oncology, Shandong Lung Cancer Institute, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China. liangjing0531@163.com.
  • 7 Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China. liyan16766@163.com.
  • 8 Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Department of Oncology, Shandong Lung Cancer Institute, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China. liyan16766@163.com.
PMID: 38183539 DOI: 10.1007/s11033-023-09056-2
Abstract

Background: PD-1 blockade has shown impressive clinical outcomes in colorectal cancers patients with high microsatellite instability (MSI-H). However, the majority of patients with colorectal Cancer who present low microsatellite instability (MSI-L) or stable microsatellites (MSS) show little response to PD-1 blockade therapy. Here, we have demonstrated that Shikonin (SK) could induce cell death of CT26 cells via classically programmed and immunogenic pathways.

Methods and results: SK promoted the membrane exposure of calreticulin and upregulated the expression of heat shock protein 70 (HSP70). The upregulation of HSP70 was dependent on ROS induced by SK and silencing of PKM2 in CT26 cells reverts ROS upregulation. Besides, SK synergizes with PD-1 blockade in CT26 tumor mice model, with the increase of intramural DC cells and CD8+ T cells. The expression of HSP70 in tumor tissue was also increased in combinational SK plus αPD-1 therapy group.

Conclusions: Our study elucidated the potential role of 'Shikonin-PKM2-ROS-Hsp70' axis in the promotion of efficacy of PD-1 blockade in CRC treatments, providing a potential strategy and targets for improving the efficacy of PD-1 blockade in colorectal Cancer.

Keywords

Colorectal cancer; Hsp70; PD-1 blockade; Shikonin; Stable microsatellites.

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