
無意味変異崩壊(NMD)の阻害により、がん細胞表面に新規抗原が提示されることが示された。


coremsg

Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense- mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD. This screen revealed disruption of kinase SMG1’s phosphorylation of UPF1 as a potent disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from truncating mutations in vivo and in vitro . Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable HLA class I-associated peptides from NMD-downregulated proteins on the surface of cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.

One Sentence Summary Disruption of the nonsense-mediated decay pathway with a newly developed SMG1 inhibitor with in-vivo activity increases the expression of T-cell targetable cancer neoantigens resulting from truncating mutations.

### Competing Interest Statement

BV, KWK, & NP are founders of Thrive Earlier Detection, an Exact Sciences Company. KWK, NP are consultants to Thrive Earlier Detection. BV, KWK, NP, SZ hold equity in Exact Sciences. BV, KWK, NP, SS and SZ, are founders of or consultants to and own equity in ManaT Bio., Haystack Oncology, Neophore, CAGE Pharma and Personal Genome Diagnostics. NP is consultant to Vidium. BV is a consultant to and holds equity in Catalio Capital Management. SZ has a research agreement with BioMed Valley Discoveries, Inc. CB is a consultant to Depuy-Synthes, Bionaut Labs, Haystack Oncology, Privo Technologies and Galectin Therapeutics. CB is a co-founder of OrisDx and Belay Diagnostics. The companies named above, as well as other companies, have licensed previously described technologies related to the work from this lab but not this paper from Johns Hopkins University. BV, KWK, NP, JDC, and SS are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. Provisional patent applications on the work described in this paper have been filed by Johns Hopkins University. The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.

Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape

がんの免疫環境を変化させる無意味変異崩壊抑制剤の同定