The immunology of renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) is the most common type of kidney cancer and comprises several subtypes with unique characteristics. The most common subtype (~70% of cases) is clear-cell RCC. RCC is considered to be an immunogenic tumour but is known to mediate immune dysfunction in large part by eliciting the infiltration of immune-inhibitory cells, such as regulatory T cells and myeloid-derived suppressor cells, into the tumour microenvironment. Several possible mechanisms have been proposed to explain how these multiple tumour-infiltrating cell types block the development of an effective anti-tumour immune response, including inhibition of the activity of effector T cells and of antigen presenting cells via upregulation of suppressive factors such as checkpoint molecules. Targeting immune suppression using checkpoint inhibition has resulted in clinical responses in some patients with RCC and combinatorial approaches involving checkpoint blockade are now standard of care in patients with advanced RCC. However, a substantial proportion of patients do not benefit from checkpoint blockade. The identification of reliable biomarkers of response to checkpoint blockade is crucial to facilitate improvements in the clinical efficacy of these therapies. In addition, there is a need for the development of other immune-based strategies that address the shortcomings of checkpoint blockade, such as adoptive cell therapies.

Key points

  • Renal cell carcinoma (RCC) tumours are heavily infiltrated by T cells and myeloid cells; however, the tumour-infiltrating T cells do not mount effective anti-tumour responses, probably owing to the suppressive activity of regulatory T cells and myeloid cells.

  • The immunosuppressed state of RCC tumours provides an opportunity to restore anti-tumour immune responses by targeting negative regulators such as immune checkpoint molecules

  • Single and double agent immune checkpoint inhibition (ICI) and combinations of immune checkpoint inhibitors (ICIs) with vascular endothelial growth factor tyrosine kinase inhibitors are now the standard of care in patients with advanced RCC.

  • Despite these important developments, only a minority of patients with RCC will obtain durable benefit from ICI therapies, underscoring the need for reliable biomarkers of response to these therapies

  • Elucidation of the mechanisms that underlie responses or resistance to ICIs will enable the rational development of combinatorial strategies aimed at improving the efficacy of these therapies

  • A better understanding of the functions of immune mediators within the tumour microenvironment in RCC could lead to the development of novel therapies.

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Fig. 1: Inflammation and immunosuppressive networks in renal cell carcinoma.
Fig. 2: Mechanisms of action of CTL4 blockade and PD1 blockade.
Fig. 3: Rationale for combining anti-VEGF therapy with immune checkpoint inhibition.

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Acknowledgements

The work of J.H.F. is supported by NIH grant R01 CA168488. The work of C.M.D.-M. is supported by NIH grant R21 CA188767.

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C.M.D.-M. and J.H.F researched the data for the article. C.M.D.-M. and B.I.R. made substantial contributions to discussions of the content. All authors wrote the article and edited or reviewed the manuscript before submission.

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Correspondence to C. Marcela Díaz-Montero or James H. Finke.

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Glossary

Type 2 T helper

A subset of CD4+ T cells that promotes innate immune responses, particularly antibody production.

Type 1 T helper

A subset of CD4+ T cells that mediates cellular immune responses.

Objective response rate

The proportion of patients with a reduction in tumour size of a predefined amount and for a minimum time period.

Microsatellite instability

(MSI). A predisposition to mutation owing to deficient mismatch repair.

Deficient mismatch repair

(dMMR). Loss of function of the mismatch repair pathway, which corrects DNA mismatches generated during DNA replication and thus prevents mutations.

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Díaz-Montero, C.M., Rini, B.I. & Finke, J.H. The immunology of renal cell carcinoma. Nat Rev Nephrol (2020). https://doi.org/10.1038/s41581-020-0316-3

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