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 to target several types of blood cancer. It works by reprogramming patients’ immune cells to target specific tumor cells. In blood cancers, CAR-T therapy works very well, but it can cause extreme responses from the patient’s immune system, which can be life threatening. In solid tumors, CAR-T therapy is much less successful because the tumors secrete molecules into the space surrounding them, which weaken the immune processes that attack cancerous cells.

Stem cells are the master cells of the body. Originating in the bone marrow, they can repair and regenerate the body’s cells. Cancer stem cells play a role in resistance to CAR-T therapy, due – in part – to their ability to renew themselves, but the role of another type of stem cell, called mesenchymal stem cells, was less clear. Mesenchymal stem cells develop into tissues that line organs and blood vessels. Although it is known that mesenchymal stem cells are present in most cancers and play a role in shaping and influencing the space around tumors, their impact on CAR-T therapy has not been studied in depth.

To find out more, Zhang et al. looked at the influence of a protein, called staniocalcin-1 (STC1), on CAR-T therapy, by studying cells grown in the laboratory and human tumor cells that had been implanted in mice.

Zhang et al. found that mesenchymal stem cells reduce the ability of CAR-T therapy to destroy cancer cells and that they needed STC1 to do this successfully. They also increased the expression of molecules that dampen the immune system, and suppressed molecules called inflammasomes, which are an important part of the way the immune system detects disease. Moreover, reducing the amount of STC1 that mesenchymal stem cells expressed restored the effectivity of CAR-T therapy.

This study increases our understanding of the way that mesenchymal stem cells affect CAR-T therapy. It has the potential to open up a new way of improving the efficiency of this treatment and of reducing the harmful side effects that it can cause.

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 treatment-related 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 with an excessive immune response that causes fever, hypotension, and respiratory insufficiency. The neurotoxicity induced by CAR-T therapy exhibits a diverse array of neurologic symptoms such as tremors, expressive aphasia, and impaired attention. The precise mechanism that causes these life-threatening side effects remains unclear (Freyer and Porter, 2020; Jiang et al., 2019). On the other hand, the success of CAR-T therapy in treating solid tumors is still very limited (Martinez and Moon, 2019). Identifying hurdles and potential mechanisms that impede the function of CAR-T cells is of vital importance to expanding its use. The immunosuppressive tumor microenvironment (TME) is one of the obstacles that diminishes the efficacy of CAR-T therapy, especially for solid tumors.

Among the many factors that can modulate TME and immune response, the impact of mesenchymal stem cell (MSC) on CAR-T therapy has been little studied. MSC is a type of adult stem cell with high proliferative activity and multidirectional differentiation capacity. However, MSCs have additional paracrine effects that are believed to underlie their therapeutic functions (Jiang and Xu, 2020). By secreting a variety of cytokines into the tissue microenvironment, it has been known that MSCs can modulate extracellular matrix, promote angiogenesis, and suppress inflammation and apoptosis (Keating, 2012; Wang et al., 2014; Regmi et al., 2019). Some MSC-secreted cytokines, such as stromal cell-derived factor 1 and stem cell factor, play important roles in hematopoietic and immune regulation (Kawaguchi et al., 2019; Markov et al., 2007). In addition, studies suggest that MSCs can modulate the function of monocytic lineages cells, especially macrophages (Németh et al., 2009; YlÖstalo et al., 2012; Choi et al., 2011). Some reports also showed that MSCs could directly affect the functionality and cellular responses of T cells, Tregs, and memory T cells (Cen et al., 2019; Tumangelova-Yuzeir et al., 2019; Luque-Campos et al., 2019).

It was reported that human mesenchymal stem cells (hMSCs) could be activated by lipopolysaccharide (LPS)-stimulated macrophages to increase the expression and secretion of stanniocalcin-1 (STC1) (Oh et al., 2014). STC1 was a mitochondria-related glycoprotein originally identified as a calcium/phosphate regulating hormone in bony fishes, and later on, it was found to be a pleiotropic factor involved in various degenerative diseases such as ocular and renal disease, as well as idiopathic pulmonary fibrosis (Yeung et al., 2012; Ohkouchi et al., 2015). STC1 could improve the cell survival and regeneration of MSCs in a paracrine fashion (Ono et al., 2015). There was also evidence suggesting that STC1 played an oncogenic role in various types of tumors (Du et al., 2011; Liu et al., 2010). Based on a retrospective study of ~1500 clinical samples, it was concluded that high STC1 expression is associated with the poor clinical outcome of breast cancer (Chang et al., 2015). It was proved that STC1 is involved in several oxidative and cancer-related signaling pathways, such as NF-κB, extracellular-signal-regulated kinase (ERK), and c-Jun NH(2)-terminal kinase (JNK) pathways (Nguyen et al., 2009; Chan et al., 2017). The expression and secretion of STC1 in cancer tissue can be stimulated by external stimuli, including external cytokines and oxidative stress (Nguyen et al., 2009). Under hypoxia conditions, STC1 could be modulated by Hypoxia-inducible factor-1 (HIF-1) to facilitate the reprogramming of tumor metabolism from oxidative to glycolytic metabolism (Yeung et al., 2005). STC1 was also reported to participate in the process of epithelial-to-mesenchymal transition, which is associated with tumor invasion and the reshape of the tumor microenvironment, as well as increasing therapy resistance (Pastushenko and Blanpain, 2019).

Considering the pleiotropic role of STC1, especially its intercellular linkage between MSCs, cancer cells, and macrophage stimulation, it is interesting to know what role it plays in connection to the functions of MSC in TME. Therefore, we generated a stable STC1 knockdown MSC cell line. With a cell co-culture model containing CAR-T cells, hMSCs, macrophages, and Pfeiffer lymphoma cells to partially mimic the tumor microenvironment together with a xenograft mice model, here we studied the impacts of MSC on CAR-T efficacy and the potential immune response change in the presence and absence of STC1.

Stem cells are believed to play critical roles in resistance to cancer therapy, which is a major contributor to poor treatment responses and tumor relapse. Previous studies have been mainly focused on the role of cancer stem cells. In the current study, we presented evidences that the presence of MSCs in TME may also be an important source of cancer treatment resistance. By modulating TME, MSCs showed a strong suppressive function on CAR-T efficacy toward lymphoma cells, and interestingly, the presence of the STC1 gene played a critical role.

The role of STC1 in cancer is paradoxical. Some reports showed that it exerts an oncogenic role, whereas other studies suggested the opposite (Chen et al., 2019). The aberrant expression of STC1 has been reported to impact various types of cancer, such as triggering tumor angiogenesis by upregulating the expression of VEGF in gastric cancer cells (He et al., 2011), causing tumorigenesis and poor clinical outcomes in ovarian, colorectal, and lung cancers (Yeung et al., 2012; Chen et al., 2019). To date, the potential roles of STC1 in immunotherapy are still largely unknown. Here, we demonstrated that the presence of STC1 is critical for MSC to exert its immunosuppressive role by inhibiting cytotoxic T cell subsets, activating some key immune suppressive/escape mechanisms, and crosstalk with other immune cells.

First, a significant downregulation of CD8⁺ T Cells together with the upregulation of CD4⁺ T helper cell subsets and Tregs indicated that the suppressed CAR-T efficacy was at least partially associated with MSC’s function in modulating the proliferation of different T-cell subsets. Since the suppression of CD8⁺ T cells was completely abrogated if knockdown STC1 in MSCs, it is clear that STC1 played a key role here. Moreover, considering that STC1 is secreted into the extracellular matrix in a paracrine manner, MSCs’ modulation of the T cell subsets is most likely indirectly via altered cytokine expression or other secondary molecules activated by STC1. In line with our study, it was recently reported that STC-1 negatively correlates with immunotherapy efficacy and T cell activation by trapping calreticulin, which abrogates membrane calreticulin-directed antigen presentation function and phagocytosis (Lin et al., 2021).

The presence of MSCs also stimulated the expression of IDO and PD-L1, two important immune-suppressive molecules. Upregulation of IDO is an endogenous feedback mechanism controlling excessive immune responses, which can be produced both by tumor cells and macrophages (Uyttenhove et al., 2003). IDO-mediated formation of immunosuppressive metabolites can inhibit T-cell proliferation and induce T-cell death through the dioxin receptor (Opitz et al., 2011; Frumento et al., 2002). PD-L1 is a well-characterized molecule of the major escape mechanism of immunotherapy by inhibiting PD-1-mediated effector T cell function and downregulating antigen tolerance (Ribas and Hu-Lieskovan, 2016). There have been numerous studies reporting the bidirectional interactions between MSCs and cancer cells, resulting in regulating the expression of PD-L1 on the surface of various cancer cells or TME (Aboulkheyr and Bigdeli, 2022; Krueger et al., 2019; O’Malley et al., 2018; Sun et al., 2018). Importantly, here we demonstrated that the upregulated expression of both IDO and PD-L1 by MSCs was much reduced if the STC1 gene was knockdown.

The paracrine activity of MSCs is now widely recognized as an important cellular mechanism to communicate with immune cells and various other cell types in TME (Teixeira et al., 2013). Consistent with previous studies, we found that the addition of hMSCs to the co-culture cell model suppressed the formation of NLRP3 inflammasome in macrophages as determined by the downregulation of some key proteins including IL-1β, the activated caspase-1, and AIM. It was reported that CD4⁺ T cells could inhibit inflammasome-mediated caspase-1 activation and IL-1β release through TNF ligands or by interferon signaling (Guarda et al., 2009). Therefore, the modulation of T-cell subsets and activation of the NLRP3 inflammasome by hMSC appear to be closely connected. Since NLRP3 inflammasome is a key factor in the neuroinflammation onset in CNS injuries (Menu and Vince, 2011), the suppression of NLRP3 inflammasome by hMSC may be potentially beneficial in reducing the exacerbated immune responses associated with CAR-T therapy.

The formation of the NLRP3 inflammasome was reported to be through NF-κB-dependent transcription of IL-1β, IL-18, and NLRP3, whereas its activation is triggered by extracellular stimuli such as lysosomal permeability, potassium efflux, and oxidative stress (Kelley et al., 2019). It has been proved that the expression and secretion of STC1 in multiple cell lines can be stimulated by external stimuli, including cytokines and oxidative stress (Nguyen et al., 2009). Considering that exogenous STC1 could be internalized by macrophages within 10 min and localizes to mitochondria and played a suppressing role in ROS generation (Wang et al., 2009), we speculated that the inhibition of NLRP3 inflammasome formation might be a feedback mechanism that occurred between macrophages and hMSC. It was reported that LPS-stimulated macrophages do stimulate the expression and secretion of STC1 in hMSCs (Oh et al., 2014). Our data further demonstrated that knockdown of STC1 deprived the function of hMSC in suppressing all the three markers used in the current study in determining NLRP3 inflammasome formation, as well as the suppression of mitochondria ROS production. These data support the idea that a feedback regulation mechanism exists between hMSC and macrophages during CAR-T therapy.

Using the Xenograft mice model, we confirmed that the tumor-killing efficacy of CAR-T could also be inhibited by hMSCs in vivo, whereas knockdown of STC1 effectively abolished the inhibition. Immunohistochemical data indicated that the downregulation of CD8⁺ T cells, upregulation of CD4⁺ T helper cell subsets, and Tregs were all dependent on the function of STC1. Need to note that the amount of the injected hMSCs was much higher than that of the in vivo situation. Nevertheless, the results give a clear indication that STC1 is critical for the immune-suppressive function of hMSC.

In summary, the present study revealed a significant impact of hMSC in suppressing CAR-T efficacy and provided evidence that the STC1 gene played a critical role in the regulation of various immune-suppressive mechanisms. A speculative schema of the signaling and interactions among hMSC, macrophage, CAR-T, and tumor cells based on our current data is shown in Figure 5. In this model, activated macrophages or stress signals during CAR-T therapy may prompt MSCs to secret STC-1 into the extracellular matrix of TME, serving as a pleiotropic factor to negatively impact the function of T cells and stimulate the expression of molecules that inactivate immune responses, ultimately providing an immunosuppressive effect of MSC. While further studies are needed to understand the detailed molecular interactions underlying, the findings we presented here are no doubt that would have potential clinical applications toward improving the efficiency of CAR-T therapy as well as reducing the excessive toxicity by modulating the level of STC1 in TME.

Figure 5

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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.

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Author details

1. Rui Zhang

   Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China

   Contribution

   Conceptualization, Formal analysis, Methodology, Writing – original draft

   Contributed equally with

   Qingxi Liu

   Competing interests

   No competing interests declared

2. Qingxi Liu

   1. State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China
   2. Qilu Institute of Technology, Shandong, China

   Contribution

   Formal analysis, Methodology

   Contributed equally with

   Rui Zhang

   Competing interests

   No competing interests declared

3. Sa Zhou

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

   Contribution

   Methodology

   Competing interests

   No competing interests declared

4. Hongpeng He

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

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

5. Mingfeng Zhao

   Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China

   Contribution

   Resources, Supervision

   For correspondence

   mingfengzhao@sina.com

   Competing interests

   No competing interests declared

6. Wenjian Ma

   1. Qilu Institute of Technology, Shandong, China
   2. College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China

   Contribution

   Conceptualization, Writing - review and editing

   For correspondence

   ma_wj@tust.edu.cn

   Competing interests

   No competing interests declared

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

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