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Cellular and Molecular Biology

“Paradoxical neoantigenic mutations”: not simply a driver vs passenger dualism

British Journal of Cancer volume 129, pages 1–2 (2023)Cite this article

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I read with great interest the recent article by Ishino and colleagues [1]. In their report, the RNF43 fs117 frameshift mutation, which was considered neoantigenic, paradoxically induced a non-inflamed tumour microenvironment and resistance to PD-1 blockade. Activation of WNT/β-catenin signalling pathway, as a consequence of this loss-of-function mutation, was shown to be the possible mechanism. Based on this particular example, the authors proposed an idea of “paradoxical neoantigenic mutations”, and called for consideration of mutations’ functional consequence in assessment of neoantigens’ impact on anti-tumour immunity. Overall, this work highlighted the possible complex interplay between the functional and immunogenic aspects of somatic mutations, which opens an interesting perspective relevant to immune-related carcinogenesis, precision oncology, and design of novel anti-tumour immunotherapy.

Although the case study of RNF43 117 fs is well evidenced by functional assays, the last piece of their argumentation which leverages bioinformatics analysis of TCGA data is not adequately rigorous and may lead to misinterpretation of their “paradoxical neoantigenic mutations” concept. The authors contrasted the driver against passenger mutations regarding the strength of correlation between mutation/neoantigen burden and immune response surrogated by a meta-gene expression score of CD8A, GZMA and PRF1. Although it was shown a difference suggesting a stronger correlation between immune response and neoantigen load attributed to passenger mutations than that attributed to drivers, the effect sizes are basically so weak thus unlikely to hold a biological significance, not to mention a clinical relevance. Besides, the results were hardly interpretable for multiple highly-mutated and immunotherapy-relevant cancer types (e.g., melanoma, lung cancer, and bladder cancer), which makes the conclusion less convincing. Moreover, this rough analysis is likely misleading by framing the “paradoxical neoantigenic mutations” concept into a simple driver vs. passenger dualism, which is probably inappropriate for the following reasons. First, the observed stronger correlation between passenger mutations and immune response is likely confounded by mutagenic processes that cause somatic hypermutation, such as defects in DNA polymerase (e.g., in uterine corpus endometrial cancer) and mismatch repair genes (e.g., in colorectal cancer), and APOBEC- mutagenesis (e.g., in cervical cancer, breast cancer, and head-and-neck cancer) [2]. Second, different mutations of a given driver gene can have distinct functional impact and interplay with anti-tumour immunity. Taking the RNF43 gene as an example, Ishino et al. reported RNF43 117 fs and 659 fs mutations were both frequently neoantigenic but associated with different immune microenvironment in MSI-high colorectal cancer tumours [1]. In a work by Thornton and colleagues, the RNF43 117 fs was shown to be a loss-of-function mutation defective in suppressing WNT signalling, which is consistent with Ishino and colleagues’ report; by contrast, the RNF43 659 fs mutation induced activation of NFκB-mediated TNF-α signalling, while the WNT signalling pathway was left unchanged [3]. Obviously, different neoantigenic driver mutations (even of the same gene) possibly induce heterogeneous net effects in anti-tumour immunity, because the interplay between immunogenicity and functional consequence may largely vary across driver gene mutations. Therefore, it could be harmful to simply consider driver neoantigenic mutations as less likely to trigger immune response than passenger neoantigenic mutations.

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References

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  1. College of Basic Medical Sciences, Medical School, Hubei Minzu University, 39 Xueyuan Road, Enshi, 445000, China

    Xiang-Yu Meng

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Meng, XY. “Paradoxical neoantigenic mutations”: not simply a driver vs passenger dualism. Br J Cancer 129, 1–2 (2023). https://doi.org/10.1038/s41416-023-02270-6

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