Abstract
The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy.
Keywords: Tyrosine kinase inhibitors, Immunomodulation, Angiogenesis, Renal cell carcinoma, Immunotherapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599454/
Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy
Re: Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy
A subgroup analysis of this last study found that patients previously treated with pazopanib showed a statistically significant increase in overall survival with nivolumab, while patients previously treated with sunitinib showed insignificant differences
Debbie
Re: Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy
Introduction
Angiogenesis, which is regulated by a fine balance between pro- and antiangiogenic signals, represents a key event in the development of tumors. In the absence of oxygen in the tumor nucleus, expression of some transcriptional factors, such as hypoxia inducible factor (HIF), is induced. HIF enhances the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). VEGF is an important inducer of angiogenesis, the expression of which is also controlled by different oncoproteins such as epidermal growth factor (EGF), K-ras, and PDGF, among others [1, 2].
Immune dysfunction has been well documented in cancer patients, including those affected by renal cell carcinoma (RCC) [3–5]. RCC patients present a shift from a type-1-mediated CD4+ T cell response producing interferon gamma (IFNγ) to a type-2 cytokine response, involving interleukins (IL) 4, 5, and 10. Type-1-mediated CD4+ T cell response is critical for the development of effective antitumor immunity, while type-2 cytokine response typically mediates humoral immunity. More specifically, tumor-specific T cell response to tumor-associated antigens MAGE-6 and EphA2 is characterized by a predominance of T cells synthesizing IL5 and IL4, together with reduced levels or a complete absence of T lymphocytes expressing IFNγ [6, 7]. However, the diminished type-1 response in RCC patients is not limited to MAGE-6 and EphA2-specific CD4+ T cells. It has also been reported that after undergoing primary tumor excision and/or immunotherapy and presenting a disease-free period, IFNγ-producing type-1 CD4+ T cells prevail in RCC patients, suggesting that tumor environment may promote a type-2 response [6]. In advanced stages of RCC, the peripheral blood lymphocyte response also changes from predominantly type 1 to type 2 after polyclonal activation [8].
Antiangiogenic molecules can inhibit many immunosuppressive mechanisms, such as regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), immunosuppressive cytokines, and others. Besides, they play a crucial role in inducing an efficient immunostimulatory antitumor response. In this respect, emerging evidence indicates that tyrosine kinase inhibitors (TKIs) modulate hematopoiesis and immune functions [9], and their effect on myelopoiesis depends on their different selectivity for c-kit and FLT3 receptors, expressed on hematopoietic stem cells and precursor cells [9, 10].
Angiogenesis, which is regulated by a fine balance between pro- and antiangiogenic signals, represents a key event in the development of tumors. In the absence of oxygen in the tumor nucleus, expression of some transcriptional factors, such as hypoxia inducible factor (HIF), is induced. HIF enhances the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). VEGF is an important inducer of angiogenesis, the expression of which is also controlled by different oncoproteins such as epidermal growth factor (EGF), K-ras, and PDGF, among others [1, 2].
Immune dysfunction has been well documented in cancer patients, including those affected by renal cell carcinoma (RCC) [3–5]. RCC patients present a shift from a type-1-mediated CD4+ T cell response producing interferon gamma (IFNγ) to a type-2 cytokine response, involving interleukins (IL) 4, 5, and 10. Type-1-mediated CD4+ T cell response is critical for the development of effective antitumor immunity, while type-2 cytokine response typically mediates humoral immunity. More specifically, tumor-specific T cell response to tumor-associated antigens MAGE-6 and EphA2 is characterized by a predominance of T cells synthesizing IL5 and IL4, together with reduced levels or a complete absence of T lymphocytes expressing IFNγ [6, 7]. However, the diminished type-1 response in RCC patients is not limited to MAGE-6 and EphA2-specific CD4+ T cells. It has also been reported that after undergoing primary tumor excision and/or immunotherapy and presenting a disease-free period, IFNγ-producing type-1 CD4+ T cells prevail in RCC patients, suggesting that tumor environment may promote a type-2 response [6]. In advanced stages of RCC, the peripheral blood lymphocyte response also changes from predominantly type 1 to type 2 after polyclonal activation [8].
Antiangiogenic molecules can inhibit many immunosuppressive mechanisms, such as regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), immunosuppressive cytokines, and others. Besides, they play a crucial role in inducing an efficient immunostimulatory antitumor response. In this respect, emerging evidence indicates that tyrosine kinase inhibitors (TKIs) modulate hematopoiesis and immune functions [9], and their effect on myelopoiesis depends on their different selectivity for c-kit and FLT3 receptors, expressed on hematopoietic stem cells and precursor cells [9, 10].
Debbie
Re: Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy
This is a study specific to cediranib (TKI) And alveolar soft part sarcoma .
http://www.cureasps.org/forum/viewtopic ... 547#p11842Abstract
The aim of the present study was to identify the target genes of cediranib and the associated signaling pathways in alveolar soft part sarcoma (ASPS)...
Debbie