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

  1. Rui Zhang
  2. Qingxi Liu
  3. Sa Zhou
  4. Hongpeng He
  5. Mingfeng Zhao  Is a corresponding author
  6. Wenjian Ma  Is a corresponding author
  1. Nankai University, China
  2. Tianjin University of Science and Technology, 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 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.

Data availability

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

  1. Rui Zhang

    Department of Hematology, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Qingxi Liu

    State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Sa Zhou

    College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Hongpeng He

    College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Mingfeng Zhao

    Department of Hematology, Nankai University, Tianjin, China
    For correspondence
    mingfengzhao@sina.com
    Competing interests
    The authors declare that no competing interests exist.
  6. 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.
    ORCID icon "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.

Reviewing Editor

  1. Ping-Chih Ho, Ludwig Institute for Cancer Research, Switzerland

Publication history

  1. Received: August 24, 2022
  2. Preprint posted: September 22, 2022 (view preprint)
  3. Accepted: February 12, 2023
  4. Accepted Manuscript published: February 13, 2023 (version 1)
  5. Accepted Manuscript updated: March 6, 2023 (version 2)
  6. Version of Record published: March 16, 2023 (version 3)
  7. Version of Record updated: March 21, 2023 (version 4)

Copyright

© 2023, Zhang et al.

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.

Metrics

  • 793
    Page views
  • 150
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Rui Zhang
  2. Qingxi Liu
  3. Sa Zhou
  4. Hongpeng He
  5. Mingfeng Zhao
  6. Wenjian Ma
(2023)
Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1
eLife 12:e82934.
https://doi.org/10.7554/eLife.82934

Further reading

    1. Cancer Biology
    2. Computational and Systems Biology
    Xiangkun Wu, Hong Yan ... Li Liang
    Research Article

    Colorectal cancer (CRC) remains a challenging and deadly disease with high tumor microenvironment (TME) heterogeneity. Using an integrative multi-omics analysis and artificial intelligence-enabled spatial analysis of whole-slide images, we performed a comprehensive characterization of TME in colorectal cancer (CCCRC). CRC samples were classified into four CCCRC subtypes with distinct TME features, namely, C1 as the proliferative subtype with low immunogenicity; C2 as the immunosuppressed subtype with the terminally exhausted immune characteristics; C3 as the immune-excluded subtype with the distinct upregulation of stromal components and a lack of T cell infiltration in the tumor core; and C4 as the immunomodulatory subtype with the remarkable upregulation of anti-tumor immune components. The four CCCRC subtypes had distinct histopathologic and molecular characteristics, therapeutic efficacy, and prognosis. We found that the C1 subtype may be suitable for chemotherapy and cetuximab, the C2 subtype may benefit from a combination of chemotherapy and bevacizumab, the C3 subtype has increased sensitivity to the WNT pathway inhibitor WIKI4, and the C4 subtype is a potential candidate for immune checkpoint blockade treatment. Importantly, we established a simple gene classifier for accurate identification of each CCCRC subtype. Collectively our integrative analysis ultimately established a holistic framework to thoroughly dissect the TME of CRC, and the CCCRC classification system with high biological interpretability may contribute to biomarker discovery and future clinical trial design.

    1. Cancer Biology
    Jiangfei Chen, Kunal Baxi ... Myron S Ignatius
    Research Article

    In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153D and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153D unexpectedly also predisposes to hedgehog expressing medulloblastomas in the kRASG12D-driven ERMS-model.