title: Depletion of CD4(+)CD25(high) regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy.
abstract: Adoptive cell transfer (ACT) immunotherapy administered with prior host immunosuppression significantly improved the anti-tumor efficacy in a murine model. However, bulk transfer of lymphocytes containing suppressor lymphocyte subsets, including regulatory T cells to mice bearing late-stage tumors impaired this anti-tumor effect. In this study, we investigated the enhanced anti-tumor efficacy by adoptive transfer of Treg-depleted autologous tumor infiltrating lymphocytes in advanced murine breast cancer. We found that, compared to bulk cell transfer, Treg-depleted cell transfer enhanced the activation and proliferation of both CD4(+) and CD8(+) T cells. Most importantly, the immune response deviated towards the Th1 response reflected by increased IFNgamma and reduced IL-4 secretion in both CD4(+) and CD8(+) T cells and an enhanced granzyme B release of CTL. Furthermore, the elicited Th1 response subsequently resulted in delayed tumor growth and prolonged mice survival as well as reduced lung metastasis in tumor-bearing nude mice. These results strongly indicated that Treg-depleted autologous cell transfer greatly enhanced Th1 type immune response, consequently leading to delayed tumor growth and reduced tumor burden. Therefore, ACT immunotherapy based on ex vivo selection of tumor-reactive lymphocytes resulted in enhanced anti-tumor immunity and provides important implications for further human studies.
authors.affiliation: Department of Immunology and Institute for Immunobiology, Shanghai Medical College of Fudan University, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Jiang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016923:Cell Death; D002455:Cell Division; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D053645:Interleukin-2 Receptor alpha Subunit