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Published on: November 7, 2015
Beneficial effects of sunitinib on tumor microenvironment and immunotherapy targeting death receptor5
Yoko Tsukita1, Tatsuma Okazaki1,2, Satoru Ebihara3
1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Abstract:
Tumor-associated blood vessels and lymphatics are abnormal and dysfunctional. These are hallmarks of the tumor microenvironment, which has an immunosuppressive nature, such as through hypoxia. Treatment with anti-death receptor5 (DR5) monoclonal antibody MD5-1, which induces tumor cell death, is a potent anti-tumor immunotherapy. Generally, MD5-1 induces cell death mainly via antigen presenting cells (APCs) and generates tumor-specific effector T cells. To date, the effects of a simultaneous functional improvement of abnormal blood vessels and lymphatics on the immune microenvironment are largely unknown. A combination therapy using sunitinib, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor inhibitor, and MD5-1 substantially inhibited tumor growth. Sunitinib improved pericyte coverage on endothelial cells and the expression levels of regulator of G-protein signaling 5, suggesting blood vessel normalization. Sunitinib also increased lymph flow from tumors to central lymph nodes, suggesting improved lymphatic function. In concordance with improved vasculature functions, sunitinib alleviated the tumor hypoxia, suggesting an improved tumor microenvironment. Indeed, the combination therapy induced strong activation of CD8+ T cells and dendritic cells in draining lymph nodes. The combination therapy reduced the ratio of immune-suppressive T regulatory cells in the tumors and draining lymph nodes. The combination therapy enhanced the numbers and activation of tumor-infiltrating CD8+ T cells. CD4 and/or CD8 depletion, or APC inhibiting experiments showed the contribution of CD8+ T cells and APCs to the combination therapy. These findings suggest that targeting blood vessels and lymphatics may have potential benefits for immunotherapy mediated by CD8+ T cells and APCs.
Insights
Combining sunitinib with anti-death receptor5 (DR5) monoclonal antibody MD5-1 normalizes tumor vasculature and enhances anti-tumor immunity. This combination therapy improves T cell activation and reduces immunosuppression, offering a promising approach for cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Vascular Biology
Background:
- Tumor vasculature and lymphatics are abnormal, creating an immunosuppressive tumor microenvironment.
- Anti-death receptor5 (DR5) antibody MD5-1 is a potent anti-tumor immunotherapy, primarily acting via antigen-presenting cells (APCs) and T cells.
- The impact of improving tumor vasculature and lymphatic function on the immune microenvironment is not well understood.
Purpose of the Study:
- To investigate the effects of combining sunitinib, a vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor inhibitor, with MD5-1 on tumor growth and the immune microenvironment.
- To determine if sunitinib-induced vascular normalization influences anti-tumor immune responses.
Main Methods:
- Combination therapy with sunitinib and MD5-1 was administered to tumors.
- Tumor growth inhibition was assessed.
- Vascular normalization markers (pericyte coverage, regulator of G-protein signaling 5 expression) and lymphatic function (lymph flow) were evaluated.
- Tumor hypoxia, immune cell populations (CD8+ T cells, dendritic cells, T regulatory cells), and their activation status in tumors and draining lymph nodes were analyzed.
- Depletion studies (CD4+, CD8+ T cells) and APC inhibition experiments were performed.
Main Results:
- The combination therapy substantially inhibited tumor growth.
- Sunitinib treatment led to blood vessel normalization and improved lymphatic function, reducing tumor hypoxia.
- This resulted in enhanced activation of CD8+ T cells and dendritic cells in draining lymph nodes.
- The combination therapy decreased the proportion of immunosuppressive T regulatory cells and increased the number and activation of tumor-infiltrating CD8+ T cells.
- CD8+ T cells and APCs were shown to be crucial for the combination therapy's efficacy.
Conclusions:
- Simultaneous normalization of tumor blood vessels and lymphatics, combined with DR5-targeted immunotherapy, significantly enhances anti-tumor immune responses.
- This combination strategy holds potential for improving CD8+ T cell and APC-mediated cancer immunotherapy by modulating the tumor microenvironment.
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