title: Autologous MUC1-specific Th1 effector cell immunotherapy induces differential levels of systemic TReg cell subpopulations that result in increased ovarian cancer patient survival.
abstract: Adoptive T cell immunotherapy using autologous lymphocytes is a viable treatment for patients with cancer and requires participation of Ag-specific CD4 and CD8 T cells. Here, we assessed the immunotherapeutic effects of autologous MUC1 peptide-stimulated CD4(+) effector cells following adoptive transfer in patients with ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4(+)/Th1 effector cell generation, we show that three monthly treatment cycles of peripheral blood T cell restimulation and intraperitoneal re-infusion selectively modulated endogenous T cell-mediated immune responses that correlated with diminished serum CA125 tumor marker levels and enhanced patient survival. One patient remains disease-free, another patient survived long-term for nearly 16 months with recurrent disease and two patients expired within 3-5 months following final infusion. Although PBL from all patients showed elevated MUC1 cytolytic activity following therapy, such responses did not correlate with therapeutic efficacy. Long-term survivors showed elevated levels of systemic memory (CD45RO) and naïve (CD45RA) CD3/CD4/CD25(+) T cells when compared to that of pre-treatment levels and similarly treated short-term survivors. Such cells co-expressed different levels of Foxp3 and CTLA-4 that resulted in progressively lower systemic Foxp3/CTLA-4 memory T cell ratios that further correlated with disease-free survival. Lastly, these patients showed elevated levels of MUC1-specific T cells expressing the CCR5 and CCR1 chemokine receptors and the chemokine CCL4 associated with Th1 cell differentiation/memory. We suggest that effective immunotherapy with autologous MUC1-stimulated CD4(+) effector cells induces differential levels of systemic "Ag-experienced" and "Ag-inexperienced" CD4/CD25(+) TReg cell subpopulations that influence long-term tumor immunity in ovarian cancer patients.
authors.affiliation: Department of Internal Medicine, Texas Tech University School of Medicine, Amarillo, TX 79106, USA. mark.dobrzanski@ttuhsc.edu
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dobrzanski
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Rewers-Felkins
authors.forename: Imelda S
authors.initials: IS
authors.lastname: Quinlin
authors.forename: Khaliquzzaman A
authors.initials: KA
authors.lastname: Samad
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Phillips
authors.forename: William
authors.initials: W
authors.lastname: Robinson
authors.forename: David J
authors.initials: DJ
authors.lastname: Dobrzanski
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Wright
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000097:blood / Q000276:immunology; D018394:CA-125 Antigen / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000097:blood / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D017493:Leukocyte Common Antigens / Q000097:blood / Q000276:immunology; D008875:Middle Aged; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D018394:CA-125 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C060192:MUC1 protein, human; D018396:Mucin-1; D017493:Leukocyte Common Antigens