What role do Mesenchymal stem cells play in tumor immunity?

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What role do Mesenchymal stem cells play in tumor immunity?

Mesenchymal stem cells ( MSCs ) are self-renewing pluripotent stem cells that regulate the phenotype and function of all immune cells involved in antitumor immunity.

MSCs modulate the antigen-presenting properties of dendritic cells, affect chemokine and cytokine production in macrophages and CD4+ T helper cells, alter the cytotoxicity of CD8+ T lymphocytes and natural killer cells, and modulate myeloid-derived Generation and expansion of suppressor cells and T-regulatory cells.

As plastic cells, MSCs determine their phenotype and function according to the cytokines of neighboring tumor-infiltrating immune cells.

Depending on the tumor microenvironment to which they are exposed, MSCs can acquire tumor-promoting and anti-tumor phenotypes that enhance or inhibit tumor growth.

Due to their tumor-homing properties, MSCs and their exosomes can be used as carriers to deliver antitumor drugs in tumor cells, reducing tumor viability and invasiveness.

Therefore, a better understanding of the signaling pathways that regulate the interaction between MSCs, immune cells and tumor cells will pave the way for the clinical application of MSCs in tumor immunotherapy.

Antitumor immunosuppression of MSCs

Some evidence suggests that tumor-associated MSCs ( CA-MSCs ) and exogenously administered MSCs promote tumor growth by

(i) preventing DC-dependent activation of naive T cells,

(ii) inducing selective activation of TAMs,

(iii) Regulate cytokine production in T helper cells;

(iv) Downregulate CTL and NK cell cytotoxicity;

(v) Promote the generation and expansion of Treg and MDSCs.

What role do Mesenchymal stem cells play in tumor immunity?

Studies have demonstrated that CA-MSCs inhibit DC-dependent activation of naive T cells in a paracrine, IL-10 and STAT-3-dependent manner.

CA-MSC-derived IL-10 inhibits DC-induced T cell proliferation by blocking the ability of DCs to provide cysteine to cognate T lymphocytes.

In addition, CA-MSC-derived IL-10 induced phosphorylation of STAT-3 in DCs, and phosphorylated STAT-3 inhibited IFN-γ activation sequence ( GAS ), which is also a cystathionase promoter sequence.

Thus, DC-derived cysteine delivery to T cells was inhibited, resulting in reduced T cell proliferation and activation, and lack of cysteine also significantly attenuated IFN-γ production in T cells.

The interaction between MSCs, M1-type and M2-type macrophages plays a crucial role in MSC-dependent regulation of tumor progression.

M1-type macrophages induce MSCs to produce an immunosuppressive MSC2 phenotype in a TNF-α-dependent manner.

The enhanced capacity of MSC2 to produce IL-6 and COX-2 induces an anti-inflammatory and pro-tumor M2 phenotype in TAMs.

Immunosuppressive cytokines produced by M2 TAMs and MSC2 downregulate antitumor immune responses, allowing uncontrolled cell proliferation.

Furthermore, the anti-inflammatory tumor microenvironment generated by M2-type TAMs is critical for MSC-dependent inhibition of tumor-infiltrating CD8+ CTLs.

MSC2 express CD39 and CD73 exonucleotidases, which hydrolyze ATP and ADP and produce high levels of adenosine in the tumor microenvironment.

Adenosine exerts an immunosuppressive effect on CD8+ CTL by binding to the adenosine-specific receptor A2A.

In addition to CTLs, CA-MSCs modulate the phenotypic, functional, and cytotoxic properties of tumor-infiltrating NK cells, and induce the production and expansion of MDSCs and Tregs, thereby attenuating antitumor immunity and supporting tumor growth and progression.

Immunomodulatory effects of exogenous MSCs

In the tumor microenvironment, MSCs are continuously exposed to growth factors and cytokines released by tumor-infiltrating immune cells, endothelial cells, and tumor cells.

Although numerous studies have demonstrated the tumor-promoting potential of MSCs, it must be noted that MSCs are not constitutively immunosuppressive cells.

In fact, MSCs are a double-edged sword in anti-tumor immunity. As plastic cells, MSCs may have different phenotypes and functions under the influence of the biological factors to which they are exposed.

MSCs may acquire pro-inflammatory ( MSC1 ) and anti-inflammatory ( MSC2 ) phenotypes, depending on local tissue concentrations of inflammatory cytokines, TNF-α and IFN-γ.

When MSCs engrafted into tissues with low levels of TNF-α and IFN-γ, they acquired a pro-inflammatory MSC1 phenotype, secreting large amounts of inflammatory cytokines ( IL-1β, IFN-α, IFN-β, TNF-α and IFN-γ). ), enhanced the phagocytic capacity of neutrophils and macrophages and the cytotoxicity of CTL and NK cells.

Conversely, when MSCs were exposed to high levels of inflammatory cytokines ( TNF-α and IFN-γ ), they acquired an immunosuppressive MSC2 phenotype characterized by anti-inflammatory cytokines ( TGF-β, IL-10, PGE2, NO , IDO, IL-1Ra ), which inhibit the effector function of inflammatory immune cells and reduce persistent inflammation.

Consistent with these findings, it was observed that the effects of exogenously administered MSCs on tumor immunity and tumor progression depended on the timing of their inoculation in tumor-bearing animals.

It was found that MSCs transplanted during the initial stages of melanoma growth had tumor suppressive effects, while MSCs injected during the advanced stages of melanoma development suppressed antitumor immunity and enhanced tumor progression.

Since low levels of inflammatory cytokines were detected in plasma samples from tumor-bearing mice 24 hours after tumor induction, and the concentrations of these inflammatory cytokines increased during tumor progression, it is conceivable that during the initial stages of melanoma development Injected MSCs acquired an anti-tumor MSC1 phenotype due to a low-inflammatory environment, while an immunosuppressive and tumor-promoting MSC2 phenotype was acquired due to increased inflammation during melanoma progression.

Potential application of MSCs in tumor immunotherapy

MSCs do not express MHC class II molecules and thus can be transplanted into MHC-mismatched recipients.

In addition, MSCs express multiple chemokine receptors, migrate to tumor tissues after injection, and participate in anti-tumor immune responses.

Therefore, several clinical studies have evaluated the antitumor properties of MSCs.

What role do Mesenchymal stem cells play in tumor immunity?

Due to their low immunogenicity and tumor-homing properties, MSCs have been explored as vehicles for the delivery of bispecific T-cell engagers, enabling specific T-cell-mediated elimination of tumor cells.

Szoor and colleagues used MSCs expressing GPC3/CD3 bispecific antibodies to target GPC3/CD3 T-cell engagers to GPC3-expressing cancer cells.

Co-culture of GPC3+ tumor cells, GPC3/CD3-expressing MSCs, and T lymphocytes results in increased IFN-γ production in GPC3-specific CD4+ T cells, activation and expansion of GPC3-specific CTLs, resulting in increased response to GPC3-expressing malignant effective killing of cells. Similar findings were observed in vivo, and these demonstrate the therapeutic potential of MSCs in HCC immunotherapy.

On the other hand, low-dose UV radiation and X-ray radiation can produce an antitumor MSC1 phenotype in MSCs and thus can be used for MSC therapy.

Furthermore, some evidence suggests that MSC-derived extracellular vesicles ( MSC EVs ) contain MSC-derived antitumor miRNAs and can serve as a potential therapeutic approach for MSC-based tumor immunotherapy.

Due to the lipid envelope, MSC EVs easily bypass all biological barriers and deliver the contents directly to target cells.

Therefore, MSC EVs can directly deliver MSC-derived antitumor miRNAs into tumor cells, thereby altering their viability, proliferation rate, and invasive characteristics.

What role do Mesenchymal stem cells play in tumor immunity?

Due to their high affinity for tumor tissues and increased resistance to most chemotherapeutic drugs, MSCs have been explored as targeted delivery agents for anticancer drugs.

A reduction in the number of lung metastases was found in melanoma-bearing animals that received MSCs containing the anticancer drug paclitaxel ( PTX ).

Layek and colleagues demonstrated that PTX-loaded nano- and glycoengineered MSCs enhanced antitumor properties against mouse ovarian cancer.

As carriers, MSCs have many advantages over other drugs.

Antitumor drug-loaded MSCs release chemotherapeutic drugs directly at primary and metastatic tumor sites without affecting adjacent tissues.

Therefore, compared with tumor-bearing animals receiving chemotherapy, experimental animals receiving drug-loaded MSCs had fewer side effects, longer half-life, and better antitumor effects.

Summary

MSCs, as plastic cells, determine their phenotype and function according to the cytokines of neighboring tumor-infiltrating immune cells.

In terms of anti-tumor immunity, it exhibits double-sided properties.

However, due to its low immunogenicity and tumor-homing properties, it shows some potential .

Genetically engineered MSCs expressing bispecific T-cell binders and producing anti-tumor miRNAs could serve as a novel therapy for tumor immunotherapy.

With the further understanding of MSC in anti-tumor immunity, it is expected that MSC can play a greater role in the application of cancer treatment.

references:

1.MesenchymalStem Cell: A Friend or Foe in Anti-Tumor Immunity. Int J Mol Sci. 2021 Nov18;22(22):12429.

What role do Mesenchymal stem cells play in tumor immunity?

(source:internet, reference only)

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