Immunotherapy of cytotoxic T cell-resistant tumors by T helper 2 cells: an eotaxin and STAT6-dependent process.
Currently most attempts at cancer immunotherapy involve the generation of CD8(+) cytotoxic T lymphocytes (CTLs) against tumor-associated antigens. Many tumors, however, have been immunoselected to evade recognition by CTLs and thus alternative approaches to cancer immunotherapy are urgently needed. Here we demonstrate that CD4(+) T cells that recognize a secreted tumor-specific antigen and exhibit a cytokine secretion profile characteristic of Th2 cells, are capable of clearing established lung and visceral metastases of a CTL-resistant melanoma. Clearance of lung metastases by the Th2 cells was found to be totally dependent on the eosinophil chemokine, eotaxin, and partially dependent on the transcription activator signal transducer and activator of transcription 6 (STAT6), with degranulating eosinophils within the tumors inducing tumor regression. In contrast, tumor-specific CD4(+) Th1 cells, that recruited macrophages into the tumors, had no effect on tumor growth. This work provides the basis for a new approach to adoptive T cell immunotherapy of cancer.
Mattes
Joerg
J
Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.
Hulett
Mark
M
Xie
Wei
W
Hogan
Simon
S
Rothenberg
Marc E
ME
Foster
Paul
P
Parish
Christopher
C
D000818:Animals; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D050800:STAT6 Transcription Factor; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D010047:Ovalbumin