Immunological features of clear-cell renal-cell carcinoma and resistance to immune checkpoint inhibitors

Abstract

The advent of immunotherapy has yielded great improvements in survival outcomes of people with clear-cell renal-cell carcinoma (ccRCC). Currently, immune checkpoint inhibitors (ICIs) are the cornerstone of treatment regimens for metastatic ccRCC. Yet a substantial group of patients do not respond to ICIs and few achieve long-term remission, indicating the presence of intrinsic and acquired resistance. The mechanisms underlying ICI resistance in ccRCC remain poorly understood, potentially owing to its unique immunological landscape compared with other immunotherapy-responsive cancers. Specifically, ccRCC is characterized by one of the highest levels of T cell infiltration across different tumours; however, high T cell infiltration does not correlate consistently with improved ICI outcomes. Moreover, the tumour mutational burden in ccRCC is relatively low, compared with that of other immunotherapy-responsive cancers, and fails to predict ICI efficacy. The limited predictive value of these commonly used markers for ICI response underscores the need for deeper exploration of the immunological mechanisms driving the antitumour immune response in ccRCC. Investigating commonalities and disparities with other immunotherapy-responsive cancer types might improve understanding of ICI resistance in ccRCC and inform the development of strategies to enhance the clinical benefits of immunotherapy. Although immune checkpoint inhibitors can prolong survival in people with clear-cell renal-cell carcinoma, disease progression is frequent. Here, the authors explore potential mechanisms that might drive intrinsic or acquired resistance to immune checkpoint inhibitors in clear-cell renal-cell carcinoma, including malignant cell-intrinsic and immune-cell factors.