Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

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].…”

“…To further define how miR-21 downregulates PPAR-α, anti-miR-21 (LNA-21) or pre-miR-21 was transfected in the 786-O cells to either inhibit or overexpress miR-21, respectively [7]. Using RT-qPCR, PPAR-α expression was not affected when miR-21 was overexpressed or downregulated (data not shown).…”

“…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.…”

Crosstalk Between Metabolism and Immune Activity Reveals Four Subtypes With Therapeutic Implications in Clear Cell Renal Cell Carcinoma

“…Accumulating evidence shows that ccRCC is normally in an immunosuppressive state, which is characterized by the high infiltration of regulatory T cells and myeloid cells with suppressive activity ( 12 , 13 ). Although immune checkpoint inhibition (ICI) therapy is supposed to be effective in restoring the antitumor immune response for ccRCC patient treatment, only a minority of ccRCC patients can acquire long-lasting benefits due to the heterogeneity of the TME ( 14 ). The development of ccRCC was also shown to be associated with metabolism, and many mutated genes were found to have roles in metabolic pathways ( 15 ).…”