Requirement for IFN-gamma, CD8+ T lymphocytes, and NKT cells in talactoferrin-induced inhibition of neu+ tumors.
We have previously shown that talactoferrin-alfa (TLF), a recombinant human lactoferrin, is an immunomodulatory protein that is active against implanted tumors, both as a single agent and in combination with chemotherapy. In this study, we show that talactoferrin is active against autochthonous tumors in a transgenic mouse line, which is more analogous to human cancers, and identify key mechanistic steps involved in the anticancer activity of oral TLF. BALB/c mice transgenic for the rat neu (ErbB2) oncogene (BALB-neuT) treated with oral TLF showed a significant delay in carcinogenesis, with 60% tumor protection relative to vehicle-treated mice at week 21. Oral TLF also showed tumor growth inhibition in wild-type BALB/c mice implanted with neu(+) mammary adenocarcinoma, with one third displaying a long-lasting or complete response. Oral TLF induces an increase in intestinal mucosal IFN-gamma production and an increase in Peyer's patch cellularity, including expansion of CD8(+) T lymphocytes and NKT cells, and the enhancement of CD8(+) T-cell cytotoxicity. In IFN-gamma knockout mice, there is an absence of the TLF-induced Peyer's patch cellularity, no expansion of CD8(+) T lymphocytes and NKT cells, and loss of TLF anticancer activity. TLF antitumor activity is also lost in mice depleted of CD8(+) T cells and in CD1 knockout mice, which lack NKT activity. Thus, the inhibition of distant tumors by oral TLF seems to be mediated by an IFN-gamma-dependent enhancement of CD8(+) T- and NKT cell activity initiated within the intestinal mucosa.
Spadaro
Michela
M
Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Curcio
Claudia
C
Varadhachary
Atul
A
Cavallo
Federica
F
Engelmayer
Jose
J
Blezinger
Paul
P
Pericle
Federica
F
Forni
Guido
G
D000230:Adenocarcinoma / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D007694:Killer Cells, Natural / Q000378:metabolism*; D007781:Lactoferrin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D010581:Peyer's Patches / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D007371:Interferon-gamma; D007781:Lactoferrin; D018719:Erb-b2 Receptor Tyrosine Kinases; C515276:talactoferrin alfa