Guanylyl cyclase C-induced immunotherapeutic responses opposing tumor metastases without autoimmunity.
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.
Snook
Adam E
AE
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 132 South Tenth St, Philadelphia, PA 19107, USA.
Stafford
Benjamin J
BJ
Li
Peng
P
Tan
Gene
G
Huang
Lan
L
Birbe
Ruth
R
Schulz
Stephanie
S
Schnell
Matthias J
MJ
Thakur
Mathew
M
Rothstein
Jay L
JL
Eisenlohr
Laurence C
LC
Waldman
Scott A
SA
D000256:Adenoviridae; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D006162:Guanylate Cyclase / Q000276:immunology* / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000276:immunology* / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D012107:Research Design
D019496:Cancer Vaccines; D018000:Receptors, Peptide; D011994:Recombinant Proteins; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled