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

Sep 24, 2026

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Research findings show mesenchymal stem cells (MSCs) are critical regulators of cancer immunotherapy resistance, specifically by restraining chimeric antigen receptor T cell (CAR-T) killing. In vitro co-culture with lymphoma cells and macrophages demonstrates markedly reduced CAR-T cytotoxicity in the presence of MSCs, including shifts toward more CD4+ and regulatory T cells and fewer CD8+ T cells. MSCs upregulate immune-suppressive mediators IDO and PD-L1 and suppress NLRP3 inflammasome components via mitochondrial reactive oxygen species release, effects reversed by stanniocalcin-1 (STC1) knockdown. In vivo xenograft results confirm MSC inhibition of CAR-T efficacy and identify STC1 as a key driver, suggesting potential for safer therapy by limiting excessive immune toxicity.

LanguageEnglish

CategoryHealthcare

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Pages17

Reading Time43 min

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Abstract

Introduction

eLife digest

ReSeaRCH aRTICLe *For correspondence: [mingfengzhao@sina.com](mingfengzhao@sina.com) (MZ); [ma_wj@tust.edu.cn](ma_wj@tust.edu.cn) (WM) †These authors contributed equally to this work Competing interest: The authors declare that no competing interests exist. Funding: See page 14 Received: 24 August 2022 Preprinted: 22 September 2022 Accepted: 12 February 2023 Published: 13 February 2023 Reviewing Editor: Ping-Chih Ho, Ludwig Institute for Cancer Research, Switzerland Copyright Zhang, Liu et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1 Rui Zhang1†, Qingxi Liu2,3†, Sa Zhou4, Hongpeng He4, Mingfeng Zhao1*, Wenjian Ma3,4* 1 Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; 2State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China; 3Qilu Institute of Technology, Shandong, China; 4College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China | 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 onchimeric antigen receptor modified T cell (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 and programmed cell death-ligand 1 which contributes to the immune-suppressive function of tumors. Moreover, MSCs suppressed key components of the NLRP3 inflammasome by modulating mitochondrial reactive oxygen species release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the stanniocalcin-1 (STC1) gene, which encodes the glycoprotein hormone STC-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 STC-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. | | --- | | Editor's evaluation
This study uncovers the contributions of MSC on modulating CAR T-cell behaviour. Based on the importance in basic biology and its immediate impact on translational potential, all reviewers are satisfied on the advances in this study. | Introduction Advances in chimeric antigen receptor modified T cell therapy (CAR-T) in recent years have shown enormous promise in cancer immunotherapy, which has produced unprecedented clinical outcomes, most notably for patients with hematologic malignancies (Singh et al., 2016; Park et al., 2018) . Despite the striking achievements, CAR-T therapy is also facing many challenges such as the treatmentrelated severe toxicity and side effects, including cytokine release syndrome (CRS) and neurotoxicity (Hong et al., 2020; Freyer and Porter, 2020) . CRS is the most common acute toxicity associated Zhang, Liu et al. eLife 2023;12:e82934. DOI: [https://doi.org/10.7554/eLife.82934](https://doi.org/10.7554/eLife.82934) 1 of 17 Research article Stem Cells and Regenerative Medicine | Cancer Biology eLife digest Immunotherapy is a type of cancer treatment that helps the immune system fight cancer. For example, chimeric antigen receptor T cell (CAR-T) therapy is used t

FAQs

How do mesenchymal stem cells affect CAR-T killing of lymphoma cells?

Mesenchymal stem cells significantly inhibit CAR-T cell-mediated cytotoxicity toward lymphoma cells. They alter T cell populations by increasing CD4+ and Treg cells while decreasing CD8+ cells.

Which mechanisms contribute to MSC-mediated suppression of CAR-T efficacy?

MSC exposure increases indoleamine 2,3-dioxygenase and programmed cell death-ligand 1 expression and suppresses components of the NLRP3 inflammasome. These effects are linked to modulation of mitochondrial reactive oxygen species release.

What role does stanniocalcin-1 (STC1) play in MSC suppression of CAR-T?

STC1 knockdown in MSCs abrogates the suppressive events that hinder CAR-T efficacy. Xenograft experiments further confirm that STC1 is critical for MSC inhibition of CAR-T function in vivo.

Sep 24, 2026

Uploaded by Himbo