Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

Abstract

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.

Immune-Associated Gene Signatures Serve as a Promising Biomarker of Immunotherapeutic Prognosis for Renal Clear Cell Carcinoma

“…Considering that ccRCC is an immunogenic and vascularized tumor ( 27 ), ICI therapy has shown great potential and has been approved by the US Food and Drug Administration (FDA) as the standard treatment for patients with early and advanced metastatic ccRCC ( 4 , 8 ). However, the ORR to ICI therapy remains low, with only a small proportion of patients achieving long-term, sustained outcomes after the treatment.…”

“…However, approximately 25% to 50% of primary patients experience recurrence five years after nephrectomy, and one-third of patients develop metastases; the overall 5-year survival rate is only 14% ( 1 – 3 ). ccRCC has distinct immunological features, such as a high degree of immune infiltration, relatively low mutational load, and relative sensitivity to anti-angiogenic therapy and immunotherapy ( 4 ).…”

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

“…Studies over the last decade have led to the concept that ccRCC, the most common and deadly type of cancer affecting the kidney, is a metabolic disease histologically characterized by large intracellular lipid deposits [3]. As ccRCC is typically highly resistant to conventional systemic therapies [2,[5][6][7], the identification of new molecular mechanisms driving tumor progression is essential for the rational design of new therapeutic strategies to cure ccRCC. In this context, we focused our attention on miR-21, an established oncogenic miRNA commonly upregulated in many solid tumors such as breast, lung, and stomach cancers and hematological malignancies [10,11].…”

“…Although ccRCC is known for abnormal lipid accumulation of cholesterol, cholesterol esters, and neutral lipids (triglycerides) [3], the underlying molecular mechanisms remain unclear. Furthermore, most patients with ccRCCs harbor chromosomal 3p loss and genomic mutations in the Von Hippel-Lindau Tumor Suppressor (VHL) allele, followed by the secondary loss of multiple tumor suppressor genes including PBRM1, SETD2, PTEN, and/or TP53 [4][5][6][7]. ccRCCs are also known to be highly resistant to conventional cytotoxic, radiation, and hormone therapies, and nephrectomy is the only therapeutic option used to cure early and local ccRCCs.…”

“…The current treatment options offered to metastatic patients include inhibitors of (i) tyrosine kinases, (ii) mTORC signaling, and (iii) immune control checkpoints. Despite the initial response, most metastatic ccRCC patients will develop resistance to these targeted therapies [4][5][6][7]. Therefore, deciphering the molecular mechanisms underlying renal tumor progression is urgently needed to develop new therapeutic strategies to cure ccRCC.…”