Suppression of Lewis lung tumor development in alpha 1,3 galactosyltransferase knock-out mice.
BACKGROUND
Humans lack the gene alpha 1,3 galactosyltransferase (GalT) and instead produce abundant cytolytic antibodies against cells bearing the antigen [gal alpha1,3 gal] (alphaGal). We have previously studied humoral anti-alphaGal responses in GalT knock-out (GalT KO) mice and shown that murine anti-alphaGal IgM, like human anti-alphaGal IgM, causes extensive complement-mediated cytolysis of GalT+ murine Lewis Lung carcinoma cells (LLCa) in vitro. Here we test the hypothesis that anti-alphaGal immune responses can inhibit the in vivo development of GalT+ tumors.


METHODS
GalT KO mice orally immunized to produce anti-alphaGal antibodies (n =52) and naïve non-immunized KO mice (n=37) were challenged s.c. with 10(5) LLCa tumor cells. Anti-alphaGal antibody titers were measured before and after LLCa challenge.


RESULTS
Anti-alphaGal IgM titers present at challenge correlated with protection from tumor development (p<0.04). Seventy-five percent of mice with titers > or = 1:1280 remained tumor-free versus 43% of naïve mice. Tumor onset was delayed in mice with circulating anti-alphaGal IgM versus naïve animals (p=0.02). LLCa challenge itself induced and augmented anti-alphaGal IgM and post-challenge titers correlated highly with protection from tumor development (p<0.001). No mice with post-challenge anti-alphaGal IgM titers > or = 1:1280 developed tumors, compared to 83% of mice lacking antibody. Inhibition studies showed that 30% of post-challenge IgM recognized LLCa antigens distinct from alphaGal. Anti-alphaGal IgG was low or undetectable both pre- and post challenge and did not affect tumor formation.


CONCLUSIONS
The finding that anti-alphaGal IgM suppresses GaIT+ tumor development in vivo supports the premise that immunotherapy using GalT expression can utilize human anti-alphaGal responses and induce significant anti-tumor effects.
Posekany
Karla J
KJ
Department of Microbiology and Immunology, The Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
Pittman
H Keith
HK
Swanson
Melvin S
MS
Haisch
Carl E
CE
Verbanac
Kathryn M
KM
D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D005260:Female; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout
D000912:Antibodies, Neoplasm; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase