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Immunogenicity in renal cell carcinoma: shifting focus to alternative sources of tumour-specific antigens

Nature Reviews Nephrology volume 19, pages 440–450 (2023)Cite this article

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Abstract

Renal cell carcinoma (RCC) comprises a group of malignancies arising from the kidney with unique tumour-specific antigen (TSA) signatures that can trigger cytotoxic immunity. Two classes of TSAs are now considered potential drivers of immunogenicity in RCC: small-scale insertions and deletions (INDELs) that result in coding frameshift mutations, and activation of human endogenous retroviruses. The presence of neoantigen-specific T cells is a hallmark of solid tumours with a high mutagenic burden, which typically have abundant TSAs owing to non-synonymous single nucleotide variations within the genome. However, RCC exhibits high cytotoxic T cell reactivity despite only having an intermediate non-synonymous single nucleotide variation mutational burden. Instead, RCC tumours have a high pan-cancer proportion of INDEL frameshift mutations, and coding frameshift INDELs are associated with high immunogenicity. Moreover, cytotoxic T cells in RCC subtypes seem to recognize tumour-specific endogenous retrovirus epitopes, whose presence is associated with clinical responses to immune checkpoint blockade therapy. Here, we review the distinct molecular landscapes in RCC that promote immunogenic responses, discuss clinical opportunities for discovery of biomarkers that can inform therapeutic immune checkpoint blockade strategies, and identify gaps in knowledge for future investigations.

Key points

  • Clear-cell renal cell carcinoma (ccRCC) tumours have a distinct pattern of genetic alterations, with fewer non-synonymous single nucleotide variants than most solid immunogenic tumours.

  • Insertion or deletion mutations are common in ccRCC, and have the potential to create a large antigen pool and therefore increase tumour immunogenicity.

  • ccRCC tumours have robust expression of endogenous retroviruses (ERVs) and transposable elements; whether ERV expression is causative, or a consequence of cancer development in humans remains controversial.

  • Expression of ERV subsets was associated with response to immune checkpoint blockade therapies in some, but not all, ccRCC datasets; several factors, including differences in methodological approaches and study cohort composition, might underlie this discrepancy.

  • Additional work to standardize the detection of insertions or deletions and ERV expression, as well as the characterization of the immune landscape of ccRCC, is required to elucidate the contribution of these mutations and transposable elements to ccRCC immunogenicity and antitumour immune responses.

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Fig. 1: Nucleotide insertion or deletion produces altered proteins associated with immunogenicity.
Fig. 2: TE activation can promote immune activation through viral mimicry or by generating a TE-associated antigen.

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Acknowledgements

The authors acknowledge support for W.K.R. from R01 CA217987, DOD W81XWH-22-1-0418 (KC210152), for A.A.D.C. from K01 CA245231 and the Forbeck foundation, and for M.M.W. from F31 CA261049.

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  1. Department of Medicine, Program in Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

    Melissa M. Wolf & W. Kimryn Rathmell

  2. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

    Aguirre A. de Cubas

  3. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA

    Aguirre A. de Cubas

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Wolf, M.M., Rathmell, W.K. & de Cubas, A.A. Immunogenicity in renal cell carcinoma: shifting focus to alternative sources of tumour-specific antigens. Nat Rev Nephrol 19, 440–450 (2023). https://doi.org/10.1038/s41581-023-00700-5

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  • DOI: https://doi.org/10.1038/s41581-023-00700-5

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