Journal of the National Cancer Institute Advance Access originally published online on June 24, 2008
JNCI Journal of the National Cancer Institute 2008 100(13):950-961; doi:10.1093/jnci/djn178
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Guanylyl Cyclase C–Induced Immunotherapeutic Responses Opposing Tumor Metastases Without Autoimmunity
Affiliations of authors: Departments of Pharmacology and Experimental Therapeutics (AES, BJS, PL, SS, SAW), Microbiology and Immunology (GT, LH, MJS, LCE), and Radiology (MT), Thomas Jefferson University, Philadelphia PA; Department of Pathology, Temple University Hospital, Philadelphia PA (RB); Inflammation Research, Amgen, Inc, Seattle, WA (JLR)
Correspondence to: Scott A. Waldman, MD, PhD, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 132 South Tenth St, Philadelphia, PA 19107 (e-mail: scott.waldman{at}jefferson.edu).
Background: One of the greatest impediments to cancer immunotherapy is the paucity of antigens that are tumor specific, sufficiently immunogenic, and shared among patients. Mucosa-restricted antigens that are expressed by tumor cells represent a novel class of vaccine targets that are characterized by immunologic privilege, which limits systemic tolerance to those antigens, and immunologic partitioning, which shields mucosae from systemic autoimmune responses. Here we defined the immunogenicity and antitumor efficacy of guanylyl cyclase C (GCC), a protein that is normally restricted to intestinal mucosa and universally expressed by metastatic colorectal cancer.
Methods: BALB/c mice (n = 197) were immunized with recombinant GCC-expressing viral vectors before (prophylactic) or after (therapeutic) a lethal challenge of GCC-expressing mouse colon cancer cells, and antitumor efficacy was monitored by quantifying metastasis and survival. Induction of autoimmunity was monitored by histopathology. Induction of GCC-specific B-cell and CD4+ and CD8+ T-cell responses were determined by enzyme-linked immunosorbent assay and ELISpot, respectively. Tolerance to GCC was quantified by comparing responses in GCC-deficient (n = 45) and wild-type (n = 69) C57BL/6 mice. Statistical tests were two-sided.
Results: Immunization with GCC-expressing viral vectors reduced the formation of metastases to liver (control vs GCC: mean = 30.4 vs 3.55 nodules, difference = 26.9 nodules, 95% confidence interval [CI] = 8.47 to 45.3 nodules; P = .008) and lung (control vs GCC: mean = 263 vs 55.7 nodules, difference = 207, 95% CI = 163 to 251; P < .001) and extended the median survival of mice with established lung metastases following therapeutic immunization (control vs GCC: 29 vs 38 days, P = .024), without autoimmunity. Antitumor efficacy reflected asymmetrical tolerance that was characterized by CD8+ T-cell, but not CD4+ T-cell or antibody, responses.
Conclusions: Immunologic partitioning together with immunologic privilege highlight the potential of mucosa-restricted antigens, particularly GCC, as therapeutic targets for metastatic cancer.
| CONTEXT AND CAVEATS Prior knowledge Guanylyl cyclase C (GCC) is a protein that is expressed in the cells that line the normal intestine and by metastatic colorectal cancer cells. Study design Mouse models of colon cancer were used to test the immunotherapeutic efficacy of GCC. Contributions Mice that were immunized with GCC had fewer colon cancer metastases to the liver and lungs and survived longer than control-immunized mice. No autoimmunity was observed. Implication GCC is a potential therapeutic target for metastatic colon cancer. Limitations The study used cell lines and mouse models of cancer. It is unknown whether the same results would be observed in human cancer.
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Manuscript received December 13, 2007; revised April 11, 2008; accepted May 2, 2008.
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