IL-6/STAT3 signaling in tumor cells restricts the expression of frameshift-derived neoantigens by SMG1 induction

Abstract

Background The quality and quantity of tumor neoantigens derived from tumor mutations determines the fate of the immune response in cancer. Frameshift mutations elicit better tumor neoantigens, especially when they are not targeted by nonsense-mediated mRNA decay (NMD). For tumor progression, malignant cells need to counteract the immune response including the silencing of immunodominant neoantigens (antigen immunoediting) and promoting an immunosuppressive tumor microenvironment. Although NMD inhibition has been reported to induce tumor immunity and increase the expression of cryptic neoantigens, the possibility that NMD activity could be modulated by immune forces operating in the tumor microenvironment as a new immunoediting mechanism has not been addressed. Methods We study the effect of SMG1 expression (main kinase that initiates NMD) in the survival and the nature of the tumor immune infiltration using TCGA RNAseq and scRNAseq datasets of breast, lung and pancreatic cancer. Different murine tumor models were used to corroborate the antitumor immune dependencies of NMD. We evaluate whether changes of SMG1 expression in malignant cells impact the immune response elicited by cancer immunotherapy. To determine how NMD fluctuates in malignant cells we generated a luciferase reporter system to track NMD activity in vivo under different immune conditions. Cytokine screening, in silico studies and functional assays were conducted to determine the regulation of SMG1 via IL-6/STAT3 signaling. Results IL-6/STAT3 signaling induces SMG1, which limits the expression of potent frameshift neoantigens that are under NMD control compromising the outcome of the immune response. Conclusion We revealed a new neoantigen immunoediting mechanism regulated by immune forces (IL-6/STAT3 signaling) responsible for silencing otherwise potent frameshift mutation-derived neoantigens.

Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells

“…It has been reported that cancers with a high frequency of NMD-insensitive frameshift mutations show increased immune infiltration and are associated with a better outcome after treatment with immune checkpoint inhibitors (27,28). Consistent with this, NMD inhibition results in strong immune responses and reduced tumor growth in vivo (22)(23)(24)(25). Our findings that NMD inhibition results in decreased tumorigenicity in the HT1080 fibrosarcoma model is fully in line with these reports.…”

“…Collectively, our results provide insights into the molecular mechanisms by which NMD activity benefits tumorigenicity of a classical cancer model system. Together with recent reports providing evidence for NMD's beneficial role in the development of a variety of different cancer types (22)(23)(24)(25), our findings suggest that in many cases, inhibition of NMD might represent a promising strategy to reduce tumor growth and prevent metastasis.…”

“…mRNAs containing frameshifting mutations can be translated into novel peptides, that can be recognized as foreign by the immune system and trigger an immune response. By degrading these mutant transcripts, NMD reduces the expression of neoantigens and therefore helps the tumor evade the immune attack (22)(23)(24)(25)(26)(27)(28). Further evidence that tumors benefit from high NMD activity comes from pan-cancer genomewide mutational studies that discovered that tumor suppressor genes preferentially accumulate NMDeliciting nonsense mutations, while oncogenes are depleted of NMD-inducing mutations (29,30).…”

“…Additionally, it has been reported that the genes encoding core NMD factors are amplified in multiple types of cancers and that this is associated with higher NMD efficiency and lower cytolytic activity (31). Moreover, it was recently shown that in tumors undergoing immunotherapy, the immunosuppressive IL-6/STAT3 signaling pathway induces SMG1 levels, and NMD activity, to suppress the expression of potent frameshift-derived neoantigens (24). Another way in which NMD can promote cancer is by degrading mRNAs encoding for truncated, though still functional, tumor suppressor proteins (32)(33)(34)(35).…”

“…There is abundant evidence supporting a pro-tumorigenic role for NMD. For instance, it has been shown that depletion of the NMD factors UPF2, UPF1 or SMG1 results in reduced in vivo tumor growth in a variety of cancer types, due to the strong anti-tumor immune response elicited by the NMD-deficient tumors (22)(23)(24)(25). mRNAs containing frameshifting mutations can be translated into novel peptides, that can be recognized as foreign by the immune system and trigger an immune response.…”