Abstract
The prognosis of metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the years with the emergence of immune checkpoint inhibitors (ICI) used alone, or in combination with another ICI, or with vascular endothelial growth factor receptor tyrosine kinase inhibitor. Although major response rates have been observed with ICI, many patients do not respond, reflecting primary resistance, and durable responses remain exceptional, reflecting secondary resistance. Factors contributing to primary and acquired resistance are manifold, including patient-intrinsic factors, tumor cell-intrinsic factors and factors associated with the tumoral microenvironment (TME). While some mechanisms of resistance are common to several tumor types, others are specific to mccRCC. Predictive biomarkers and alternative strategies are needed to overcome this resistance. This review provides an overview of the major ICI resistance mechanisms, highlights the potential of the TME to induce resistance to ICI, and discusses the predictive biomarkers available to guide therapeutic choice.
Highlights
Kidney cancer accounts for 3%-5% of all cancers and is the seventh and tenth most frequently diagnosed malignancy amongst men and women respectively
In the NIVOREN ancillary cohort, CD163 (M2 macrophages) with higher densities in the invasive margin was associated with better progression free survival (PFS) (HR = 0.69, P = 0.016) but not overall survival (OS) (P = 0.5) in patients treated with nivolumab[70]
TIM-3 As discussed above, TIM-3 and PD-1 co-expression on CD8 T cells is associated with worse outcomes including higher TNM stage, larger tumor size and lower PFS[97]. These findings argue for a therapeutic strategy targeting Tim-3 alone, or in combination with anti-PD-1/PD-L1
Summary
Kidney cancer accounts for 3%-5% of all cancers and is the seventh and tenth most frequently diagnosed malignancy amongst men and women respectively. A short study on 15 mccRCC patients published in 2018 showed that IDO-1 overexpression (> 10%) in tumor endothelial cells was more frequent in case of response to nivolumab and associated with a better PFS. This would suggest that IDO could be used as a biomarker[90]. ICI: immune checkpoint inhibitors; ccRCC: clear cell renal cell carcinoma; JAK-STAT: Janus Kinase - signal transducers and activators of transcription; PD-L1: programmed cell death ligand 1; MHC: major histocompatibility complex; IDO1: indoleamine 2,3-dioxygenase 1; PPARγ: peroxisome proliferator-activated receptor gamma; PTEN: phosphatase and TENsin homolog. TME: tumor micro environment; ICI: immune checkpoint inhibitors; ccRCC: clear cell renal cell carcinoma; PBRM1: protein polybromo-1; PD1: programmed cell death 1; PD-L1: programmed cell death ligand 1; LAG3: lymphocyte-activation gene 3; TIM3: 1-5 T cell immunoglobulin mucin-3
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