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

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Cancer is characterized by the acquisition of immune escape mechanisms (1). Cancer immunotherapy with immune checkpoint inhibitors (ICIs) improves dysfunctional cytotoxic effector CD8+ T cells, leading to tumor regression (2, 3). ICIs have been demonstrated to be effective against diverse cancer types, leading to a paradigm shift in cancer treatment (4-6). However, more than half of patients do not respond to ICIs. Therefore, the need to identify biomarkers to predict the response to ICIs is imperative in clinical settings. Despite numerous basic and clinical studies on biomarkers, accurate prediction of response remains elusive.

Somatic mutation-derived neoantigens, which can be recognized as non-self, elicit strong immune responses (7, 8). Thus, neoantigens are presumed to induce an inflamed tumor microenvironment (TME), which is essential for the ICI response, and the number of neoantigens is reportedly correlated with the inflamed TME (8-10). Therefore, tumor mutational burden (TMB) is one of the predictive biomarker candidates for ICIs (9, 11, 12). However, there have been some conflicting data about this neoantigen theory (13, 14). Tumors also evade antitumor immunity through “immune editing”, which involves the elimination of highly immunogenic tumor cells or mutation of their own human leukocyte antigen (HLA) molecules to decrease antigen presentation (15-18). Furthermore, in the process of accumulating somatic mutations, certain cancer signaling pathways promote immune evasion (19-24).

In this study, we evaluated 88 MSI-H colorectal cancer patients and identified that fs mutations in the driver gene RNF43 were shared neoantigens among patients, as previously reported (25). Tumors with neoantigens derived from these RNF43 frameshift (fs) mutations tended to have an inflamed TME, which is consistent with the neoantigen theory. However, our study revealed variations in the TME among the different RNF43 frameshift mutations. RNF43 is a tumor suppressor gene that suppresses the WNT/β-catenin signaling pathway, which previously reported to suppress antitumor immunity (20, 23). We demonstrated that RNF43 117fs is a loss-of-function mutation that activates the WNT/β-catenin signaling pathway, while RNF43 659fs was comparable to RNF43 WT (26-30). In addition, the WNT/β-catenin signaling pathway activation resulting from loss-of-function fs mutations led to a noninflamed TME even in the presence of neoantigens and resistance to PD-1 blockade in mouse models. We also validated these results using The Cancer Genome Atlas (TCGA) datasets, and demonstrated that passenger rather than driver gene mutations were related to the inflamed TME. Thus, even if such functional driver gene mutations become neoantigens, patients with these neoantigens could have a noninflamed TME because of gene functions.

In summary, we propose a novel concept of “paradoxical neoantigenic mutations” that can induce the noninflamed TME due to their original gene functions, despite deriving neoantigens. Our findings highlight the importance of evaluating the qualities as well as quantities of neoantigenic mutations.

 

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