Partial CD4 depletion reduces regulatory T cells induced by multiple vaccinations and restores therapeutic efficacy.
OBJECTIVE
A single vaccination of intact or reconstituted-lymphopenic mice (RLM) with a granulocyte macrophage colony-stimulating factor-secreting B16BL6-D5 melanoma cell line induces protective antitumor immunity and T cells that mediate the regression of established melanoma in adoptive immunotherapy studies. We wanted to study if multiple vaccinations during immune reconstitution of the lymphopenic host would maintain a potent antitumor immune response.


METHODS
RLM were vaccinated multiple times over a 40-day period. Spleens were isolated from these mice, activated in vitro, and adoptively transferred into mice bearing 3-day experimental pulmonary metastases.


RESULTS
Multiple vaccinations, rather than boosting the immune response, significantly reduced therapeutic efficacy of adoptive immunotherapy and were associated with an increased frequency and absolute number of CD3+CD4+Foxp3+ T regulatory (T(reg)) cells. Anti-CD4 administration reduced the absolute number of T(reg) cells 9-fold. Effector T-cells generated from anti-CD4-treated mice were significantly (P < 0.0001) more therapeutic in adoptive transfer studies than T cells from multiply vaccinated animals with a full complement of CD4+ cells.


CONCLUSIONS
These results suggest that CD4+ T(reg) cells limit the efficacy of multiple vaccinations and that timed partial depletion of CD4+ T cells may reduce suppression and "tip-the-balance" in favor of therapeutic antitumor immunity. The recent failure of large phase III cancer vaccine clinical trials, wherein patients received multiple vaccines, underscores the potential clinical relevance of these findings.
LaCelle
Michael G
MG
Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Oregon Health and Science University, Portland, Oregon, USA.
Jensen
Shawn M
SM
Fox
Bernard A
BA
D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D019496:Cancer Vaccines / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007107:Immune System; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008545:Melanoma / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D017252:CD3 Complex; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor