Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth

AbstractGlioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-β secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-β acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB–IL6–STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-β were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.

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Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Cancers ◽

10.3390/cancers13040870 ◽

2021 ◽

Vol 13 (4) ◽

pp. 870

Author(s):

Tomasz M. Grzywa ◽

Magdalena Justyniarska ◽

Dominika Nowis ◽

Jakub Golab

Keyword(s):

T Cells ◽

Tumor Growth ◽

Progenitor Cells ◽

Cancer Progression ◽

Immune Evasion ◽

Transforming Growth Factor ◽

Early Stage ◽

Interleukin 10 ◽

Erythroid Progenitor ◽

Erythroid Progenitor Cells

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

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Response to Comment on “Local Accumulation of FOXP3+ Regulatory T Cells: Evidence for an Immune Evasion Mechanism in Patients with Large Condylomata Acuminata”

The Journal of Immunology ◽

10.4049/jimmunol.181.7.4433-a ◽

2008 ◽

Vol 181 (7) ◽

pp. 4433.2-4434

Author(s):

Yuchun Cao ◽

Jie Zhao ◽

Bo Huang

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Immune Evasion ◽

Condylomata Acuminata ◽

Immune Evasion Mechanism ◽

Local Accumulation

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Abstract 3547: Disruption of Galectin1-glycan interaction impairs tumor growth and metastasis in breast cancer by disarming the immunosuppressive capacity of regulatory T cells

10.1158/1538-7445.am2012-3547 ◽

2012 ◽

Author(s):

Tomas D'Alotto Moreno ◽

Diego O. Croci ◽

Juan P. Cerliani ◽

Sebastian L. Dergan Dylon ◽

Ivan Mascanfroni ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Tumor Growth ◽

Tumor Growth And Metastasis

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Depletion of CD4+CD25high regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy

Cancer Biology & Therapy ◽

10.4161/cbt.8.1.7131 ◽

2009 ◽

Vol 8 (1) ◽

pp. 66-72 ◽

Cited By ~ 21

Author(s):

Lin Xu ◽

Wei Xu ◽

Zhenggang Jiang ◽

Feng Zhang ◽

Yiwei Chu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Regulatory T Cells ◽

Tumor Growth ◽

Adoptive Immunotherapy ◽

Tumor Infiltrating Lymphocytes ◽

Infiltrating Lymphocytes

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Regulatory T cells mediate resistance to radiotherapy in head and neck squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.70 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. 70-70 ◽

Cited By ~ 1

Author(s):

Ayman Oweida ◽

Laurel Darragh ◽

Shilpa Bhatia ◽

David Raben ◽

Lynn Heasley ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Tumor Growth ◽

Head And Neck ◽

Critical Role ◽

Growth Delay ◽

Functional Changes ◽

Treg Depletion

70 Background: Head and neck tumors are highly enriched in regulatory T cells which dampen the response to radiotherapy by creating an immune-inhibitory microenvironment. We explored mechanisms of Treg infiltration and assessed their modulation by RT in murine models of HNSCC. Methods: Mechanisms of Treg infiltration were investigated in murine HNSCC tumors using whole genome sequencing and flow cytometry. Mice were treated with anti-CTLA-4, anti-CD-25 and/or anti-PD-L1 alone and in combination with RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T cell populations. Multiplex ELISA was performed for assessment of cytokines. RNA Sequencing was performed to interrogate mechanisms of response and resistance to treatment. Results: Treatment with anti-CD-25 concurrently with RT led to significant tumor growth delay, enhanced T cell cytotoxicity, decreased Tregs and improved survival. In contrast CTLA-4 blockade did not affect tumor growth or survival. Treg depletion induced an influx of CD8 and CD4 T cells when combined with RT. In addition, Treg depletion in combination with RT transformed myeloid populations decreasing M2 macrophages and MDSCs and increasing M1 macrophages. Mechanistically, tumors secrete CCL20, a potent Treg chemoattractant responsible for creating a highly immunuosuppressive tumor microenvironment and potentially responsible for treatment resistance. Conclusions: These data reveal a critical role for regulatory T cells in mediating resistance to RT. Targeted depletion of Tregs represents an important mechanism of sensitizing tumors to RT. Our data support the design of clinical trials integrating targeted Treg inhibitors in the standard of care for cancer patients receiving RT.

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