Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1

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Abstract

Stem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on CAR-T immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that CAR-T cell-mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSCs caused an increase of CD4+ T cells and Treg cells but a decrease of CD8+ T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death-ligand 1 (PD-L1) which contributes to the immune-suppressive function of tumors. Moreover, MSCs suppressed key components of the NLRP3 inflammasome by modulating mitochondrial ROS release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the STC1 gene, which encodes the glycoprotein hormone staniocalcin-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo and STC1 played a critical role. These data revealed a novel function of MSC and staniocalcin-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from the excessive immune response.

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All data generated or analysed during this study are included in the manuscript. Source Data files have been provided for Figures 1, 2, 3 and 4.

Article and author information

Author details

Rui Zhang

Department of Hematology, Nankai University, Tianjin, China

Competing interests
The authors declare that no competing interests exist.
Qingxi Liu

State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China

Competing interests
The authors declare that no competing interests exist.
Sa Zhou

College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China

Competing interests
The authors declare that no competing interests exist.
Hongpeng He

College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China

Competing interests
The authors declare that no competing interests exist.
Mingfeng Zhao

Department of Hematology, Nankai University, Tianjin, China

For correspondence
mingfengzhao@sina.com

Competing interests
The authors declare that no competing interests exist.
Wenjian Ma

College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China

For correspondence
ma_wj@tust.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3392-1549

Funding

National Key Research and Development Program of China (2018YFA0901702)

Wenjian Ma

Shandong Key Research and Development Program (2019GSF107088)

Qingxi Liu

National Science foundation of Shandong (ZR202111220001)

Wenjian Ma

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal experiments and procedures were approved by the Ethics Committee of Tianjin First Central Hospital (approval#2021-SYDWLL-000301).

Human subjects: Ethical approval and informed consent were obtained. Patients with lymphoma and Healthy donors agreed to participate in this experiment within a clinical trial at the Department of Hematology at Tianjin First Central Hospital (Tianjin, China) with autologous CAR-T 19 cells (ChiCTR-ONN-16009862; Tianjin First Central Hospital Medical Ethics Committee) in accordance with the World Medical Association medical research guidelines. Peripheral blood samples were obtained from healthy male donors (n = 3) in Tianjin First Central Hospital.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.