Increased frequency of suppressive regulatory T cells and T cell-mediated antigen loss results in murine melanoma recurrence.
Therapeutic treatment of large established tumors using immunotherapy has yielded few promising results. We investigated whether adoptive transfer of tumor-specific CD8(+) T cells, together with tumor-specific CD4(+) T cells, would mediate regression of large established B16BL6-D5 melanomas in lymphopenic Rag1(-/-) recipients devoid of regulatory T cells. The combined adoptive transfer of subtherapeutic doses of both TRP1-specific TCR transgenic Rag1(-/-) CD4(+) T cells and gp100-specific TCR transgenic Rag1(-/-) CD8(+) T cells into lymphopenic recipients, who received vaccination, led to regression of large (100-400 mm(2)) melanomas. The same treatment strategy was ineffective in lymphoreplete wild-type mice. Twenty-five percent of mice (15/59) had tumors recur (15-180 d postregression). Recurrent tumors were depigmented and had decreased expression of gp100, the epitope targeted by the CD8(+) T cells. Mice with recurrent melanoma had increased CD4(+)Foxp3(+) TRP1-specific T cells compared with mice that did not show evidence of disease. Importantly, splenocytes from mice with recurrent tumor were able to suppress the in vivo therapeutic efficacy of splenocytes from tumor-free mice. These data demonstrate that large established tumors can be treated by a combination of tumor-specific CD8(+) and CD4(+) T cells. Additionally, recurrent tumors exhibited decreased Ag expression, which was accompanied by conversion of the therapeutic tumor-specific CD4(+) T cell population to a Foxp3(+)CD4(+) regulatory T cell population.
Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR 97213, USA.
Shawn M
SM
Jensen
Christopher G
CG
Twitty
Levi D
LD
Maston
Paul A
PA
Antony
May
M
Lim
Hong-Ming
HM
Hu
Ulf
U
Petrausch
Nicholas P
NP
Restifo
Bernard A
BA
Fox
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D045744:Cell Line, Tumor; D005260:Female; D018655:Lymphocyte Count; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D010088:Oxidoreductases / Q000096:biosynthesis / Q000172:deficiency; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology*; D058951:gp100 Melanoma Antigen / Q000378:metabolism
D000951:Antigens, Neoplasm; D008562:Membrane Glycoproteins; D058951:gp100 Melanoma Antigen; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse