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Epitope-targeted cytotoxic T cells mediate lineage-specific antitumor efficacy induced by the cancer mucosa antigen GUCY2C

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Abstract

Guanylyl cyclase C (GUCY2C) is the index cancer mucosa antigen, an emerging class of immunotherapeutic targets for the prevention of recurrent metastases originating in visceral epithelia. GUCY2C is an autoantigen principally expressed by intestinal epithelium, and universally by primary and metastatic colorectal tumors. Immunization with adenovirus expressing the structurally unique GUCY2C extracellular domain (GUCY2CECD; Ad5-GUCY2C) produces prophylactic and therapeutic protection against GUCY2C-expressing colon cancer metastases in mice, without collateral autoimmunity. GUCY2C antitumor efficacy is mediated by a unique immunological mechanism involving lineage-specific induction of antigen-targeted CD8+ T cells, without CD4+ T cells or B cells. Here, the unusual lineage specificity of this response was explored by integrating high-throughput peptide screening and bioinformatics, revealing the role for GUCY2C-directed CD8+ T cells targeting specific epitopes in antitumor efficacy. In BALB/c mice vaccinated with Ad5-GUCY2C, CD8+ T cells recognize the dominant GUCY2C254–262 epitope in the context of H-2Kd, driving critical effector functions including interferon gamma secretion, cytolysis ex vivo and in vivo, and antitumor efficacy. The ability of GUCY2C to induce lineage-specific responses targeted to cytotoxic CD8+ T cells recognizing a single epitope mediating antitumor efficacy without autoimmunity highlights the immediate translational potential of cancer mucosa antigen–based vaccines for preventing metastases of mucosa-derived cancers.

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Abbreviations

CMA:

Cancer mucosa antigen

GMP:

Guanosine monophosphate

GUCY2C:

Guanylyl cyclase C

PKG:

Protein kinase G

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Acknowledgments

We would like to thank Dr. Mathew Thakur and the members of the Small Animal Imaging Core Facility, Thomas Jefferson University, for their assistance in PET/CT imaging. Financial support was provided by the National Institutes of Health (CA75123, CA95026) and Targeted Diagnostic and Therapeutics Inc. (to S.A.W.); Measey Foundation Fellowship (to A.E.S.); S.A.W is the Samuel M.V. Hamilton Endowed Professor. This project is funded, in part, by a grant from the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions. S.A.W is the chair of the Data Safety Monitoring Board for the C-Cure Trial™ sponsored by Cardio Biosciences, and the chair (uncompensated) of the Scientific Advisory Board to Targeted Diagnostics and Therapeutics, Inc., which provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work.

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  1. Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA, 19107, USA

    Adam E. Snook, Michael S. Magee, Glen P. Marszalowicz, Stephanie Schulz & Scott A. Waldman

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  1. Adam E. Snook
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  2. Michael S. Magee
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  3. Glen P. Marszalowicz
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  4. Stephanie Schulz
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  5. Scott A. Waldman
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Correspondence to Adam E. Snook.

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Snook, A.E., Magee, M.S., Marszalowicz, G.P. et al. Epitope-targeted cytotoxic T cells mediate lineage-specific antitumor efficacy induced by the cancer mucosa antigen GUCY2C. Cancer Immunol Immunother 61, 713–723 (2012). https://doi.org/10.1007/s00262-011-1133-0

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