IL-4-transduced tumor cell vaccine induces immunoregulatory type 2 CD8 T lymphocytes that cure lung metastases upon adoptive transfer.
Vaccinations with tumor cells engineered to produce IL-4 prolonged survival and cured 30% of mice bearing pulmonary metastases, an effect abrogated by in vivo depletion of T cells. Vaccination induced type 2 T cell polarization in both CD4 and CD8 T lymphocyte subsets. We focused on the antitumor activity exerted by type 2 CD8+ T cells (Tc2) activated by IL-4 tumor cell vaccination. Tc2 lymphocytes lacked in vitro tumor cytotoxicity, but released IL-4 upon stimulation with tumor cells, as shown by limiting dilution analysis of the frequencies of tumor-specific pCTL and of CD8 cells producing the cytokine. In vivo fresh purified CD8+ T lymphocytes from IL-4-vaccinated mice eliminated 80-100% of lung metastases when transferred into tumor-bearing mice. CD8+ lymphocytes from IL-4-vaccinated IFN-gamma knockout (KO), but not from IL-4 KO, mice cured lung metastases, thus indicating that IL-4 produced by Tc2 cells was instrumental for tumor rejection. The antitumor effect of adoptively transferred Tc2 lymphocytes needed host CD8 T cells and AsGM1 leukocyte populations, and partially granulocytes. These data indicate that Tc2 CD8+ T cells exert immunoregulatory functions and induce tumor rejection through the cooperation of bystander lymphoid effector cells. Tumor eradication is thus not restricted to a type 1 response, but can also be mediated by a type 2 biased T cell response.
Rodolfo
M
M
Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. rodolfo@istitutotumori.mi.it
Zilocchi
C
C
Accornero
P
P
Cappetti
B
B
Arioli
I
I
Colombo
M P
MP
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D018014:Gene Transfer Techniques; D006098:Granulocytes / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008136:Longevity; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011956:Receptors, Cell Surface; D012190:Retroviridae / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
D019496:Cancer Vaccines; D002352:Carrier Proteins; D016207:Cytokines; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D015847:Interleukin-4