Abstract
Immunotherapy has revolutionized the treatment landscape for many cancer types. The treatment for renal cell carcinoma (RCC) has especially evolved in recent years, from cytokine-based immunotherapies to immune checkpoint inhibitors. Although clinical benefit from immunotherapy is limited to a subset of patients, many combination-based approaches have led to improved outcomes. The success of such approaches is a direct result of the tumor immunology knowledge accrued regarding the RCC microenvironment, which, while highly immunogenic, demonstrates many unique characteristics. Ongoing translational work has elucidated some of the mechanisms of response, as well as primary and secondary resistance, to immunotherapy. Here, we provide a comprehensive review of the RCC immunophenotype with a specific focus on how preclinical and clinical data are shaping the future of immunotherapy.
Highlights
Discrepancies can exist between disease sites, as Renal cell carcinoma (RCC) metastatic lesions displayed a greater number of tumor-associated macrophages (TAMs) but a decreased immunosuppressive M2skewing compared to the primary tumor [52], and intra-tumoral macrophages appear to be decreased after treatment with bevacizumab [53]
Clinical features associated with response to immune checkpoint inhibitors (ICIs) in RCC include a high neutrophil-tolymphocyte ratio (NLR), both at baseline and after treatment [148], International Metastatic RCC Database Consortium (IMDC) poor/intermediaterisk patients, and the Memorial Sloan Kettering Cancer Center (MSKCC) poor-risk group [149,150], between the MSKCC risk groups there was no difference in Tumor mutational burden (TMB)
To optimize the therapeutic landscape and future clinical trial design for RCC patients, it is essential to understand the basic and translational tumor immunology science that laid the foundation for these treatment breakthroughs [212]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. In the recently published phase III KEYNOTE-564 trial, adjuvant pembrolizumab (anti-PD-1) demonstrated definitive DFS benefit in patients at high risk of recurrence after nephrectomy [17], offering another promising treatment option in this setting. In CheckMate 214, International Metastatic RCC Database Consortium (IMDC) intermediate/poor-risk ccRCC patients treated with nivolumab plus ipilimumab (anti-CTLA-4) had significant benefit in OS, PFS, quality of life, and subsequent treatmentfree survival compared to those treated with sunitinib [24,25]. Cells 2021, 10, 3231 treated patients identified enrichment of PD-L1 and M2 TAMs in the patient cluster with the worst outcomes [26] These preclinical findings make the ICI/TKI combination a promising therapeutic approach in patients with advanced ccRCC, leading to clinical benefit that has been validated in several clinical trials [27,28,29,30,31]. Immune checkpoint inhibitor (ICI), tyrosine kinase inhibitor (TKI), median overall survival (mOS), months (mo), confidence interval (CI), not estimable (NE), hazard ratio (HR), median progression free survival (mPFS), overall response rate (ORR), complete response (CR), partial response (PR), and not reached (NR)
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