Regression of a mammary adenocarcinoma in STAT6-/- mice is dependent on the presence of STAT6-reactive T cells.
Polarization of the immune response toward a type 1 cytokine profile has been posited to be associated with a therapeutic antitumor immune response. STAT6-/- mice are unable to generate a type 2 immune response, and instead mount an enhanced type 1 response. STAT6-/- mice are significantly more resistant to 4T1, a mammary adenocarcinoma cell line, resisting a 10-fold higher tumor dose compared with wild-type (wt) BALB/c mice. An analysis of the T cells from tumor-bearing STAT6-/- mice revealed that they contained a population primed by a peptide (STAT6(531-539)) of the STAT6 protein expressed in 4T1. The adoptive transfer of T cells from STAT6(531-539)-vaccinated STAT6-/- mice significantly reduced the number of 4T1 pulmonary metastases in recipient mice. Additionally, the role of these STAT6(531-539)-reactive T cells against s.c. 4T1 tumor challenge was determined by tumor-challenging wt BALB/c mice reconstituted with STAT6-/- bone marrow, thereby assessing whether a polarized type 1 immune response in the absence of STAT6-reactive T cells was sufficient to reject a 4T1 tumor challenge. T cells from the STAT6-/- bone marrow chimeras failed to recognize the STAT6(531-539), and these mice proved to be as susceptible as wt BALB/c mice to 4T1 challenge. This demonstrated that the absence of STAT6(531-539)-reactive T cells correlated with the inability to reject 4T1 challenge. Additionally, these data emphasize that the enhanced ability to mount a type 1-polarized immune response is inconsequential if a sufficient antitumor immune response is not primed by the tumor.
Jensen
Shawn M
SM
Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR 97213, USA.
Meijer
Sybren L
SL
Kurt
Robert A
RA
Urba
Walter J
WJ
Hu
Hong-Ming
HM
Fox
Bernard A
BA
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D019264:Adoptive Transfer; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D007279:Injections, Subcutaneous; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D050800:STAT6 Transcription Factor; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000008:administration & dosage / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000637:transplantation
D019496:Cancer Vaccines; D010446:Peptide Fragments; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators