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Review
. 2020 Jul 2;3(3):454-471.
doi: 10.20517/cdr.2020.16. eCollection 2020.

Resistance to cancer immunotherapy in metastatic renal cell carcinoma

Marco Moreira  1   2 , Cedric Pobel  3   4   2 , Nicolas Epaillard  3 , Audrey Simonaggio  3 , Stéphane Oudard  3   5 , Yann-Alexandre Vano  1   3
Affiliations
Review

Resistance to cancer immunotherapy in metastatic renal cell carcinoma

Marco Moreira et al. Cancer Drug Resist. .

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.

Keywords: Tumor microenvironment; clear cell renal cell carcinoma; immune checkpoint inhibitor; immune checkpoint inhibitor resistance.

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Conflict of interest statement

Not applicable.

Figures

Figure 1
Figure 1
Main mechanisms of resistance to current immunotherapy in renal cell carcinoma. The main mechanisms of resistance to current immunotherapy can be divided into three major categories: tumor cell intrinsic factors, patient intrinsic factors and factors related to the tumor microenvironment. Here, some medical interventions to counteract these resistances are described. CAF: cancer associated fibroblasts; CDK4/CDK6: cyclin dependent kinase 4/cyclin dependent kinase 6; CSF1R: colony stimulating factor 1 receptor; CTLA4: cytotoxic T-lymphocyte antigen-4; CTK: cytokine; IDO: indoleamine 2 3-dioxygenase; IFN: interferon; HLA: human leukocyte antigen; ICI: immune checkpoint inhibitor; LAG3: lymphocyte-activation gene 3; MAPK: mitogen-activated protein kinase; MDSCs: myeloid derived suppressor cells; MHC: major histocompatibility complex; PD-1: programmed cell death 1; PTEN: phosphatase and TENsin homolog; RIG-1: retinoic acid-inducible gene 1; STING: stimulator of IFN genes; TAMs: tumor associated macrophages; TIM3: 1-5 T cell immunoglobulin mucin-3; TME: tumor Microenvironment
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