CD8+ T Cell-Dependent Antitumor Activity In Vivo of a Mass Spectrometry-Identified Neoepitope despite Undetectable CD8+ Immunogenicity In Vitro.

Autor:	Gillig MA; Department of Immunology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT., Brennick CA; Department of Immunology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT., George MM; Department of Immunology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT., Balsbaugh JL; Proteomics and Metabolomics Facility, Center for Open Research Resources and Equipment, University of Connecticut, Storrs, CT., Shcheglova TV; Department of Immunology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT., Mandoiu II; Department of Computer Science and Engineering, University of Connecticut, Storrs, CT., Rosales T; Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN., Baker BM; Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN., Srivastava PK; Department of Immunology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT., Karandikar SH; Department of Immunology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2023 Dec 15; Vol. 211 (12), pp. 1783-1791.
DOI:	10.4049/jimmunol.2300356
Abstrakt:	Identification of neoepitopes that can control tumor growth in vivo remains a challenge even 10 y after the first genomics-defined cancer neoepitopes were identified. In this study, we identify a neoepitope, resulting from a mutation in the junction plakoglobin (Jup) gene (chromosome 11), from the mouse colon cancer line MC38-FABF (C57BL/6). This neoepitope, Jup mutant (JupMUT), was detected during mass spectrometry of MHC class I-eluted peptides from the tumor. JupMUT has a predicted binding affinity of 564 nM for the Kb molecule and a higher predicted affinity of 82 nM for Db. However, whereas structural modeling of JupMUT and its unmutated counterpart Jup wild-type indicates that there are little conformational differences between the two epitopes bound to Db, large structural divergences are predicted between the two epitopes bound to Kb. Together with in vitro binding data with RMA-S cells, these data suggest that Kb rather than Db is the relevant MHC class I molecule of JupMUT. Immunization of naive C57BL/6 mice with JupMUT elicits CD8-dependent tumor control of a MC38-FABF challenge. Despite the CD8 dependence of JupMUT-mediated tumor control in vivo, CD8+ T cells from JupMUT-immunized mice do not produce higher levels of IFN-γ than do naive mice. The structural and immunological characteristics of JupMUT are substantially different from those of many other neoepitopes that have been shown to mediate tumor control. (Copyright © 2023 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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