Blockade of TGF-beta enhances tumor vaccine efficacy mediated by CD8(+) T cells.
Though TGF-beta inhibition enhances antitumor immunity mediated by CD8(+) T cells in several tumor models, it is not always sufficient for rejection of tumors. In this study, to maximize the antitumor effect of TGF-beta blockade, we tested the effect of anti-TGF-beta combined with an irradiated tumor vaccine in a subcutaneous CT26 colon carcinoma tumor model. The irradiated tumor cell vaccine alone in prophylactic setting significantly delayed tumor growth, whereas anti-TGF-beta antibodies alone did not show any antitumor effect. However, tumor growth was inhibited significantly more in vaccinated mice treated with anti-TGF-beta antibodies compared to vaccinated mice without anti-TGF-beta, suggesting that anti-TGF-beta synergistically enhanced irradiated tumor vaccine efficacy. CD8(+) T-cell depletion completely abrogated the vaccine efficacy, and so protection required CD8(+) T cells. Depletion of CD25(+) T regulatory cells led to the almost complete rejection of tumors without the vaccine, whereas anti-TGF-beta did not change the number of CD25(+) T regulatory cells in unvaccinated and vaccinated mice. Though the abrogation of CD1d-restricted NKT cells, which have been reported to induce TGF-beta production by MDSC through an IL-13-IL-4R-STAT6 pathway, partially enhanced antitumor immunity regardless of vaccination, abrogation of the NKT cell-IL-13-IL-4R-STAT-6 immunoregulatory pathway did not enhance vaccine efficacy. Taken together, these data indicated that anti-TGF-beta enhances efficacy of a prophylactic vaccine in normal individuals despite their not having the elevated TGF-beta levels found in patients with cancer and that the effect is not dependent on TGF-beta solely from CD4(+)CD25(+) T regulatory cells or the NKT cell-IL-13-IL-4R-STAT-6 immunoregulatory pathway.
Takaku
Shun
S
Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Terabe
Masaki
M
Ambrosino
Elena
E
Peng
Judy
J
Lonning
Scott
S
McPherson
John M
JM
Berzofsky
Jay A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry; D018793:Interleukin-13 / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015847:Interleukin-4 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014611:Vaccination
D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; C508018:Il2ra protein, mouse; D018793:Interleukin-13; D053645:Interleukin-2 Receptor alpha Subunit; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D016212:Transforming Growth Factor beta; D015847:Interleukin-4