Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite...

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Predicting immune checkpoint inhibitor (ICI) efficacy requires robust biomarkers.
• High tumor mutational burden (TMB) is often associated with ICI response, but conflicting data exist.
• Investigating the functional impact of neoantigenic mutations on the tumor microenvironment (TME) is crucial.

Purpose of the Study:

• To analyze the function of neoantigenic mutations and their impact on ICI efficacy.
• To explore the role of RNF43 mutations in microsatellite instability-high (MSI-H) colorectal cancers.
• To validate findings using The Cancer Genome Atlas (TCGA) datasets.

Main Methods:

• Evaluation of 88 MSI-H colorectal cancer samples.
• Analysis of neoantigenic mutation function and influence on programmed cell death 1 (PD-1) blockade.
• Validation using TCGA datasets.

Main Results:

• Frameshift RNF43 mutations were identified as common neoantigenic mutations in MSI-H tumors.
• Loss-of-function RNF43 mutations promoted a non-inflamed TME via WNT/β-catenin pathway activation.
• RNF43 loss-of-function conferred resistance to PD-1 blockade, even in tumors with abundant neoantigens.
• Passenger gene mutations, not driver mutations, correlated with an inflamed TME across various cancer types.

Conclusions:

• A novel concept of "paradoxical neoantigenic mutations" is proposed.
• These mutations can induce a non-inflamed TME by retaining original gene functions, despite neoantigen generation.
• The quality of neoantigenic mutations, not just quantity, is significant for ICI efficacy.