TGF-βR inhibitor SB431542 restores immune suppression induced by regulatory B–T cell axis and decreases tumour burden in murine fibrosarcoma
| Autor: | Bhavani S. Shankar, Kavitha Premkumar |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research Fibrosarcoma T cell medicine.medical_treatment Regulatory B cells Immunology chemical and pharmacologic phenomena Dioxoles Lymphocyte Activation T-Lymphocytes Regulatory CD19 Mice 03 medical and health sciences 0302 clinical medicine Immune system Antigens CD Transforming Growth Factor beta medicine Animals Immunology and Allergy Cytotoxic T cell IL-2 receptor Cell Proliferation B-Lymphocytes Regulatory Mice Inbred BALB C biology Chemistry CD28 Forkhead Transcription Factors Immunotherapy Interleukin-10 Tumor Burden medicine.anatomical_structure Oncology Benzamides biology.protein Cancer research Female Receptors Transforming Growth Factor beta Spleen 030215 immunology |
| Zdroj: | Cancer Immunology, Immunotherapy. 70:153-168 |
| ISSN: | 1432-0851 0340-7004 |
| DOI: | 10.1007/s00262-020-02666-w |
| Popis: | The contribution of immune cells in soft tissue sarcomas (STS) is not completely known and understanding their role is very essential for employing immunotherapy strategies. Here, we show that murine fibrosarcoma-conditioned medium promoted total spleen cell proliferation but inhibited T cell responses to mitogenic and allo-antigen-mediated stimulation. This increased proliferation was found to be in B cells resulting in generation of Breg further leading to Treg population. This was found to be the same in vitro and in vivo. The phenotype of these B cells was CD19+CD81+CD27+CD25+PD-L1hi and they secreted both IL-10 and TGF-β. These tumor evoked Bregs (tBreg), when co-cultured with B depleted T cells, suppressed their proliferation in response to anti-CD3/CD28 stimulation. tBreg-induced suppression of T cell responses was not abrogated by the inhibition or neutralization of IL-10 but by the small molecule inhibitor of TGFβ Receptor type I, SB431542. While SB531542 per se was not cytotoxic to tumor cells, administration of SB431542 in tumor-bearing mice (TBM) significantly reduced the tumor burden. In addition, the treatment significantly reduced Treg cells and rescued proliferation of T cells in response to mitogen and allo-antigen. Collectively, our results identify that tumor evoked Breg cells mediate T cell immune suppression through TGFβ-mediated pathway and that targeting the Breg–Treg axis can be potentially used as an immunotherapy agent. |
| Databáze: | OpenAIRE |
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