Lineage-specific T-cell responses to cancer mucosa antigen oppose systemic metastases without mucosal inflammatory disease.

Authors

Adam E. Snook, Thomas Jefferson UniversityFollow
Peng Li, Thomas Jefferson UniversityFollow
Benjamin J Stafford, Thomas Jefferson UniversityFollow
Elizabeth J Faul, Thomas Jefferson UniversityFollow
Lan Huang, Thomas Jefferson UniversityFollow
Ruth C Birbe, Temple University HospitalFollow
Alessandro Bombonati, Thomas Jefferson UniversityFollow
Stephanie Schulz, Thomas Jefferson UniversityFollow
Matthias J. Schnell, Thomas Jefferson UniversityFollow
Laurence C. Eisenlohr, Thomas Jefferson UniversityFollow
Scott A. Waldman, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

4-15-2009

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Cancer Research

Volume 69, Issue 8, April 2009, Pages 3537-3544.

The published version is available at DOI: 10.1158/0008-5472.CAN-08-3386. Copyright © American Association for Cancer Research

Abstract

Cancer mucosa antigens are emerging as a new category of self-antigens expressed normally in immunologically privileged mucosal compartments and universally by their derivative tumors. These antigens leverage the established immunologic partitioning of systemic and mucosal compartments, limiting tolerance opposing systemic antitumor efficacy. An unresolved issue surrounding self-antigens as immunotherapeutic targets is autoimmunity following systemic immunization. In the context of cancer mucosa antigens, immune effectors to self-antigens risk amplifying mucosal inflammatory disease promoting carcinogenesis. Here, we examined the relationship between immunotherapy for systemic colon cancer metastases targeting the intestinal cancer mucosa antigen guanylyl cyclase C (GCC) and its effect on inflammatory bowel disease and carcinogenesis in mice. Immunization with GCC-expressing viral vectors opposed nascent tumor growth in mouse models of pulmonary metastasis, reflecting systemic lineage-specific tolerance characterized by CD8(+), but not CD4(+), T-cell or antibody responses. Responses protecting against systemic metastases spared intestinal epithelium from autoimmunity, and systemic GCC immunity did not amplify chemically induced inflammatory bowel disease. Moreover, GCC immunization failed to promote intestinal carcinogenesis induced by germ-line mutations or chronic inflammation. The established role of CD8(+) T cells in antitumor efficacy, but CD4(+) T cells in autoimmunity, suggests that lineage-specific responses to GCC are particularly advantageous to protect against systemic metastases without mucosal inflammation. These observations support the utility of GCC-targeted immunotherapy in patients at risk for systemic metastases, including those with inflammatory bowel disease, hereditary colorectal cancer syndromes, and sporadic colorectal cancer.

Recommended Citation

Snook, Adam E.; Li, Peng; Stafford, Benjamin J; Faul, Elizabeth J; Huang, Lan; Birbe, Ruth C; Bombonati, Alessandro; Schulz, Stephanie; Schnell, Matthias J.; Eisenlohr, Laurence C.; and Waldman, Scott A., "Lineage-specific T-cell responses to cancer mucosa antigen oppose systemic metastases without mucosal inflammatory disease." (2009). Department of Pharmacology and Experimental Therapeutics Faculty Papers. Paper 30.
https://jdc.jefferson.edu/petfp/30

PubMed ID

19351847