Oral ingestion of Lentinula edodes mycelia extract inhibits B16 melanoma growth via mitigation of regulatory T cell-mediated immunosuppression.
Mitigation of regulatory T cell-mediated immunosuppression is crucial for optimal in vivo anti-tumor immune responses. In this study, we examined the anti-tumor effect induced by oral ingestion of an immunomodulating diet comprised of Lentinula edodes mycelia (L.E.M.) extract. C57BL/6 mice were inoculated subcutaneously in the footpad with B16 melanoma and fed L.E.M. extract. Ingestion of L.E.M. extract significantly inhibited tumor growth, and this in vivo anti-tumor effect was not observed in nude mice, suggesting a T cell-dependent mechanism. In addition, ingestion of L.E.M. extract led to significant restoration of H-2K(b) -restricted and melanoma-reactive T cells in the spleen and draining lymph nodes of melanoma-bearing mice. Flow cytometry analysis revealed that the percentage of Foxp3(+) CD4(+) T cells increased in spleen and draining lymph nodes in melanoma-bearing mice, but decreased significantly with ingestion of L.E.M. extract. Importantly, selective depletion of CD8(+) T cells abolished the L.E.M.-induced anti-tumor effect, whereas that of CD4(+) T cells or CD25(+) cells showed no additive influence on the effect. Real-time PCR analysis revealed that ingestion of L.E.M. extract by melanoma-bearing mice decreased the level of Foxp3 mRNA within the tumor tissues, and lowered plasma transforming growth factor (TGF)-β. Furthermore, an in vitro assay revealed that an immunosuppressive activity of CD4(+) T cells from melanoma-bearing mice was canceled by ingestion of L.E.M. extract. Our results indicate that oral ingestion of L.E.M. extract restores immune responses of class I-restricted and melanoma-reactive CD8(+) T cells in melanoma-bearing mice, presumably by a mitigation of regulatory T cells-mediated immunosuppression.
Central R&D Laboratory, Kobayashi Pharmaceutical Co. Ltd., Ibaragi, Osaka, Japan. ko.tanaka@kobayashi.co.jp
Kousuke
K
Tanaka
Satoru
S
Ishikawa
Yasunori
Y
Matsui
Makoto
M
Tamesada
Nanae
N
Harashima
Mamoru
M
Harada
D000284:Administration, Oral; D000818:Animals; D005260:Female; D007108:Immune Tolerance; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D020942:Shiitake Mushrooms; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta
Cancer Res. 2005 Jun 15;65(12):5027-30
15958544
Immunity. 2007 Jul;27(1):145-59
17613255
Eur J Immunol. 2010 Jan;40(1):142-52
19943263
J Nat Med. 2010 Jan;64(1):16-23
19711151
Agric Biol Chem. 1990 Feb;54(2):479-87
1368512
J Immunol. 2009 Apr 15;182(8):4499-506
19342621
Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17073-8
18952840
Eur J Immunol. 2004 Feb;34(2):336-44
14768038
J Exp Med. 1997 Feb 3;185(3):453-9
9053445
Biol Pharm Bull. 2009 Jul;32(7):1215-9
19571388
Nat Med. 1998 Mar;4(3):328-32
9500607
Cancer Immunol Immunother. 1998 Dec;47(4):198-204
9875672
Nat Med. 2004 Sep;10(9):909-15
15340416
J Immunol. 2007 Feb 15;178(4):2018-27
17277105
J Immunol Methods. 2008 Apr 20;333(1-2):167-79
18295790
Cancer Lett. 1982 Nov-Dec;17(2):109-14
6891904
J Clin Invest. 2007 Sep;117(9):2570-82
17710230
Jpn J Cancer Res. 2002 Aug;93(8):911-6
12716469
Science. 2008 Oct 10;322(5899):271-5
18845758
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43
16344461
Nat Med. 2004 Sep;10(9):942-9
15322536
J Clin Invest. 2004 Jul;114(2):280-90
15254595
Semin Cancer Biol. 2006 Apr;16(2):115-23
16376102
Cancer Res. 1999 Jul 1;59(13):3128-33
10397255
Cancer Lett. 1985 May;27(1):1-6
4039972
Int J Cancer. 2010 Aug 15;127(4):768-79
20518013
Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12198-203
11027314
Science. 2007 Jul 13;317(5835):256-60
17569825
J Exp Med. 2009 Feb 16;206(2):343-57
19204112
Clin Cancer Res. 2008 May 15;14(10):3156-67
18483384
Cancer Res. 2009 May 15;69(10):4309-18
19435909
Nat Med. 1998 Mar;4(3):321-7
9500606