Besides, ccRCC4 tumors showed no response to sunitinib, which was related to high levels of expression of markers of Tregs (i.e., FOXP3, IL-10., and TGF-). optimization of combination therapy and development of individualized therapy for advanced ccRCC. = 0.0001) and objective response rates (ORR) (31 vs. 13%; = 0.0001), and did not lead to significantly increasing or new adverse reactions (117). Therefore, the combination of IFN- and bevacizumab is currently recommended by the European Society for Medical Oncology (ESMO) guidelines as a first-line option for mRCC patients with favorable risk (category 3B) or intermediate risk (category 2C) (116). Despite this, VEGF/VEGFR inhibitors may also have immunosuppressive effects in some cases. For example, increased infiltration of CD4+ Foxp3+ Tregs and upregulation of PD-L1 expression were observed in primary RCC patients treated with sunitinib (118). Several studies have also shown that high doses of anti-angiogenic agents could lead to hypoxia Rabbit polyclonal to TNFRSF10D of the tumor microenvironment and upregulation of the CXCR4/CXCL12 axis and HIF- levels due to excessive pruning of tumor vessels, which facilitates the recruitment of TAMs, MDSCs, and Tregs (Figure 2C) (119, 120). Based on these observations, we propose the following conjecture: moderate doses of VEGF/VEGFR inhibitors are beneficial for enhancing anti-tumor immune responses, while excessive doses can cause hypoxia-induced immunosuppression, which could partially explain the development of acquired resistance and progression in some mRCC patients treated with anti-angiogenic agents alone. Therefore, the dual modulatory effects of anti-angiogenic drugs on the TIME should be considered when choosing the individualized treatment in patients with advanced ccRCC. It is also worth exploring how to determine the optimal dose of anti-angiogenic drugs and how to reduce their immunosuppressive effects. Immunomodulatory Effects of mTOR Inhibitors As a downstream effector of the PI3K/Akt pathway, mTOR regulates various modulators of cell growth (e.g., eIF4E, S6K1, and cyclin-D) and pro-angiogenic factors (e.g., HIF, bFGF, and VEGF) (121, 122). Several studies have shown that the levels of mTOR pathway-related proteins (including p70S6K, p-mTOR, PI3K, and pAkt) in RCC were significantly higher than those in normal kidney tissues, and HPGDS inhibitor 2 positively correlated with tumor progression (122). mTOR inhibitors can effectively inhibit tumor proliferation and angiogenesis in RCC and are recommended as second-line therapies for patients with mRCC (115). In fact, mTOR inhibitors were first approved for the prevention of immune rejection in solid organ transplant recipients because of their immunosuppressive properties (123). Thus, it is hypothesized that mTOR inhibitors may also have immunomodulatory functions in the tumor microenvironment. An increased percentage of Tregs and MDSCs, as well as a decreased frequency of CD56bright NK cells and DCs, were found in mRCC patients treated with the mTOR inhibitor everolimus (124). These results suggest that mTOR inhibitors can promote immunosuppression of the tumor microenvironment in RCC, which limits their anti-cancer efficacy. As cyclophosphamide (CTX) was previously shown to selectively suppress Tregs and restore effector function of Teff cells and NK cells (125), a phase I clinical study attempted to assess whether CTX can counteract the immunosuppression of everolimus (126). CTX combined with everolimus significantly reduced the percentage of Tregs and MDSCs and increased the frequency of CD8+ T cells and DC subsets in mRCC patients (126). Currently, the efficacy and safety of this combination therapy are being evaluated in a phase II trial. Thus, using treatments that modulate immunosuppressive cells or enhance the immune response may improve the therapeutic effect of mTOR inhibitors in mRCC. Genomic Changes in ccRCC that Influence the TIME ccRCC has HPGDS inhibitor 2 relatively unique genomic features compared to other RCC types, namely chromosomal 3p deletion (>90%), chromosomal 5q gain (>67%), and somatic mutations closely related to 3p HPGDS inhibitor 2 deletion events, including mutations in (127). Other common genomic alterations in ccRCC include chromosome 14q deletions, mutations, and mutations (31). Analyses of tumor evolutionary trajectories have shown significant intra-tumor heterogeneity in ccRCC.