Abstract
Simple SummaryClear cell renal cell carcinomas (ccRCC) have several distinct immunological features, including a high degree of immune infiltration and relatively low mutational burdens, the resistance to cytotoxic chemotherapy, and relative sensitivity to anti-angiogenic therapy and immunotherapies. Immune checkpoint inhibitor (ICI) therapy has become standard care in the treatment of ccRCC, but a better understanding of the molecular and cellular characteristics of ccRCC is needed to truly optimize the use of ICI therapy. With a focus on cancer immunology, we summarize the clinical trials of ICIs in ccRCC, the molecular and cellular correlates of these clinical trials, and the single-cell RNA sequencing studies to provide a comprehensive overview of the immune landscape within the ccRCC tumor microenvironment, in particular in the context of ICI therapy. We will discuss potential molecular and cellular biomarkers that can be used to predict therapeutic responses in ccRCC patients.Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.
Highlights
Renal cell carcinomas (RCC) arise from the renal epithelium and account for more than 90% of cancers occurring in the kidney [1]
RCC is histologically classified into subtypes, of which clear cell RCC is the most common–accounting for more than 80% of RCCs, followed by papillary RCC and chromophobe RCC [1,4]. ccRCC is characterized by the abundance of glycogen and lipids in the cytosol [1,4]
Following interleukin 2 (IL-2) therapy, clinical treatment of ccRCC moved more towards the use of tyrosine kinase inhibitors (TKIs) targeting VEGFA/VEGF and its receptor (VEGFR) pathway and neoangiogenesis, including sunitinib, sorafenib, and cabozantinib for treating ccRCC patients [74,75,76]
Summary
Renal cell carcinomas (RCC) arise from the renal epithelium and account for more than 90% of cancers occurring in the kidney [1]. In studies evaluating ICI in combination with anti-VEGF or TKIs as a first-line therapy, it significantly improved the clinical outcome in patients with ccRCC, showing an objective response rate (ORR) of 50 to 59%, including 4 to 12% complete response (CR) rates, depending on experimental settings [21,22,23,24,25]. Current basic, translational, and clinical research underscores the need to further investigate the tumor immune microenvironment in ccRCC to predict patient outcomes, to identify patients who are likely to respond to immunotherapy, and/or to determine new immunotherapy modalities to treat patients who are not responsive to current ICI therapy. The ORRs of the two cytokines are in general low in ccRCC patients, and the major hurdle for their clinical use lies in the significant toxicities affecting multiple major organs [72,73]
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