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Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Targeting neoantigens conserved across organs and species overcomes tumor immune escape
Guillaume Mestrallet1, Ross W Ward1, Matthew Brown1
1Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Abstract:
Neoantigen-targeted immunotherapies hold promise for cancer treatment, but current personalized approaches are time-consuming and costly. Here, we identify neoantigens encoded by Ptprs and Igf2r that are shared across murine mismatch repair-deficient colorectal and breast tumors and unexpectedly conserved in human colorectal, endometrial, gastric, and prostate cancers. These neoantigens elicit spontaneous, organ-spanning CD8+ T cell-mediated memory responses that are enhanced by immune checkpoint blockade. Vaccination with mRNA/lipid nanoparticles encoding these conserved neoantigens suppresses tumor growth across prophylactic and therapeutic models, including checkpoint-resistant orthotopic tumors. Tumor rejection is accompanied by antigen spreading, abscopal effects, and infiltration by clonally diverse T cells, dendritic cells, and MHC I/II+ macrophages producing CXCL9/10, CCL5/8, and TNF. Tumor cells also show activation of innate and adaptive pathways, including MHC and ISGs overexpression. Our results uncover a conserved anti-tumor immune mechanism and support the development of off-the-shelf neoantigen vaccines across tissues and species.
Insights
This study identifies conserved neoantigens in Ptprs and Igf2r that trigger potent anti-tumor immunity. Off-the-shelf vaccines using these neoantigens show promise for treating multiple cancers.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Personalized neoantigen immunotherapies are effective but costly and time-consuming.
- Identifying shared neoantigens across tumor types can streamline cancer treatment development.
Purpose of the Study:
- To identify conserved neoantigens in Ptprs and Igf2r across murine and human cancers.
- To evaluate the therapeutic potential of these neoantigens in cancer vaccines.
Main Methods:
- Identification of shared neoantigens in Ptprs and Igf2r.
- Assessment of CD8+ T cell responses and immune checkpoint blockade effects.
- Vaccination studies using mRNA/lipid nanoparticles in prophylactic and therapeutic cancer models.
Main Results:
- Neoantigens from Ptprs and Igf2r are conserved in human colorectal, endometrial, gastric, and prostate cancers.
- These neoantigens induce spontaneous, organ-spanning CD8+ T cell memory responses.
- Vaccination suppressed tumor growth, enhanced immune cell infiltration, and activated anti-tumor pathways.
Conclusions:
- A conserved anti-tumor immune mechanism involving Ptprs and Igf2r neoantigens was uncovered.
- Off-the-shelf neoantigen vaccines are a viable strategy for broad cancer treatment across species.
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