(1) Meraviglia-Crivelli D (2) Villanueva H (3) Zheleva A (4) Villalba-Esparza M (5) Moreno B (6) Menon AP (7) Calvo A (8) Cebollero J (9) Barainka M (10) de Los Mozos IR (11) Huesa-Berral C (12) Pastor F

Molecular cancer

Meraviglia and Crivelli et al. identified an IL-6/STAT3/SMG1 axis-dependent immunoediting mechanism that limits the expression of potent frameshift neoantigens by nonsense-mediated mRNA decay (NMD) and dampens immune response. SMG1 kinase expression correlated with lower immune infiltration and worse survival in multiple patients with cancer. In mouse models, genetic/pharmacological inhibition of SMG1 led to higher T cell infiltration, significant reduction of tumor progression, and improved ICB response in a CD8+ T cell-dependent manner. Tumors with reduced SMG1 expression displayed alternative TCR repertoires and higher T cell expansion.

Contributed by Shishir Pant

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.

Author Info: (1) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Instituto de Investigaci—n Sanitaria de Navarra (IDISN

Author Info: (1) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Instituto de Investigaci—n Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, 31008, Pamplona, Spain. (2) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Instituto de Investigaci—n Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, 31008, Pamplona, Spain. (3) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Instituto de Investigaci—n Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, 31008, Pamplona, Spain. (4) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Instituto de Investigaci—n Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, 31008, Pamplona, Spain. Department of Pathology, Yale University School of Medicine, New Haven, CT, 06510, USA. (5) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. (6) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Instituto de Investigaci—n Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, 31008, Pamplona, Spain. (7) IDISNA, CIBERONC, Program in Solid Tumors (CIMA), Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Avenida P’o XII, 55, 31008, Pamplona, Spain. (8) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Instituto de Investigaci—n Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, 31008, Pamplona, Spain. (9) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Instituto de Investigaci—n Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, 31008, Pamplona, Spain. (10) Gene Therapy Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. Department of Personalized Medicine, NASERTIC, Government of Navarra, 31008, Pamplona, Spain. (11) Department of Physics and Applied Mathematics, School of Science, University of Navarra, E-31008, Pamplona, Navarra, Spain. (12) Molecular Therapeutics Program, Center for Applied Medical Research, CIMA, University of Navarra, 31008, Pamplona, Spain. fpasrodri@unav.es. Instituto de Investigaci—n Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, 31008, Pamplona, Spain. fpasrodri@unav.es. Department of Molecular Therapies, CIMA (Center for Applied Medical Research) University of Navarre, Av. de P’o XII, 55, 31008, Pamplona, Spain. fpasrodri@unav.es.

Citation: Mol Cancer 2022 Nov 28 21:211 Epub11/28/2022

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/36443756

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