CD8+ T Cell-Dependent Antitumor Activity In Vivo of a Mass Spectrometry-Identified Neoepitope despite Undetectable
Marc A Gillig1, Cory A Brennick1, Mariam M George1
1Department of Immunology, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT.
Abstract:
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.
Insights
Researchers identified a novel cancer neoepitope, Jup mutant (JupMUT), from a junction plakoglobin gene mutation. This neoepitope controls tumor growth in mice, highlighting new avenues for cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Identifying effective cancer neoepitopes for tumor control remains a significant challenge.
- Genomics-defined neoepitopes have shown promise, but their clinical application is still evolving.
Purpose of the Study:
- To identify and characterize a novel neoepitope from a mouse colon cancer model.
- To investigate the potential of this neoepitope in eliciting anti-tumor immunity.
Main Methods:
- Mass spectrometry of MHC class I-eluted peptides from MC38-FABF colon cancer cells.
- Structural modeling and in vitro binding assays to assess neoepitope-MHC interactions.
- In vivo immunization studies in C57BL/6 mice to evaluate tumor control.
Main Results:
- A neoepitope, Jup mutant (JupMUT), derived from a junction plakoglobin gene mutation was identified.
- JupMUT showed preferential binding to the Kb MHC class I molecule.
- Immunization with JupMUT induced CD8-dependent tumor control in a mouse colon cancer model.
Conclusions:
- JupMUT represents a distinct class of neoepitopes with unique structural and immunological properties.
- This neoepitope demonstrates potential for developing novel cancer immunotherapies.
- Further research into JupMUT's characteristics could advance neoepitope-based cancer treatments.
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