Abstract
Immune checkpoint inhibitors (ICIs) are currently a first-line treatment option for clear cell renal cell carcinoma (ccRCC). However, recent clinical studies have shown that a large number of patients do not respond to ICIs. Moreover, only a few patients achieve a stable and durable response even with combination therapy based on ICIs. Available studies have concluded that the response to immunotherapy and targeted therapy in patients with ccRCC is affected by the tumor immune microenvironment (TIME), which can be manipulated by targeted therapy and tumor genomic characteristics. Therefore, an in-depth understanding of the dynamic nature of the TIME is important for improving the efficacy of immunotherapy or combination therapy in patients with advanced ccRCC. Here, we explore the possible mechanisms by which the TIME affects the efficacy of immunotherapy and targeted therapy, as well as the factors that drive dynamic changes in the TIME in ccRCC, including the immunomodulatory effect of targeted therapy and genomic changes. We also describe the progress on novel therapeutic modalities for advanced ccRCC based on the TIME. Overall, this review provides valuable information on the optimization of combination therapy and development of individualized therapy for advanced ccRCC.
Highlights
As one of the most common malignancies of the genitourinary system, renal cell carcinoma (RCC) affects ∼400,000 people worldwide each year, resulting in ∼175,000 deaths [1]
The phase 3 COMPARZ study showed that high infiltration of tumorassociated macrophages (TAMs) was associated with poor prognosis in metastatic renal cell carcinoma (mRCC) patients treated with VEGFR-TKIs, suggesting that TAMs may contribute to the resistance of RCC to anti-angiogenic agents [102]
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
Summary
As one of the most common malignancies of the genitourinary system, renal cell carcinoma (RCC) affects ∼400,000 people worldwide each year, resulting in ∼175,000 deaths [1]. Granulocyte-macrophage colonystimulating factor (GM-CSF) secreted by tumor cells mediates the proliferation of MDSCs through the pSTAT5 pathway, and induces them to secrete pro-angiogenic proteins including IL-8 and matrix metalloproteinase-9 (MMP-9), resulting in reduced sensitivity to VEGF/VEGFR inhibitors in RCC (Figure 2A) [95].
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