title: Autoimmune thyroiditis as an indicator of autoimmune sequelae during cancer immunotherapy.
abstract: Improving cancer immunotherapy by targeting T cell network also triggers autoimmunity. We disrupted regulatory T cell (Treg) function to probe the balance between breast cancer vaccination and autoimmune thyroiditis (EAT) in four models, with particular attention to MHC-associated susceptibility, EAT induction with mouse thyroglobulin (mTg) without adjuvant, and tolerance to Her-2/neu in transgenic mice. 1) In EAT-resistant BALB/c mice, Treg depletion enhanced tumor regression, and facilitated mild thyroiditis induction. 2) In Her-2 tolerant C57BL/6 mice expressing HLA-DR3, an EAT-susceptibility allele, Her-2 DNA vaccinations must follow Treg depletion for (Her-2xDR3)F(1) mice to resist tumor challenge; thyroiditis incidence was moderated by the EAT-resistant IA(b) allele. 3) In neu tolerant, EAT-resistant BALB/c mice, implanted neu(+) tumor also regressed only after Treg depletion and DNA vaccinations. Tumor immunity was long-term, providing protection from spontaneous tumorigenesis. In all three, immune stimuli from concurrent tumor regression and EAT development have a noticeable, mutually augmenting effect. 4) In Treg-depleted, EAT-susceptible CBA/J mice, strong tumor protection was established by immunization with a cell vaccine. mTg injections led to greater thyroiditis incidence and severity. Combination models with MHC class II diversity should facilitate autoimmunity risk assessment and management while generating tumor immunity.
authors.affiliation: Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. ykong@med.wayne.edu
authors.forename: Yi-chi M
authors.initials: YC
authors.lastname: Kong
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Jacob
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Flynn
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Elliott
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005802:Genes, MHC Class II / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects*; D051379:Mice; D008808:Mice, Inbred CBA; D011110:Polymorphism, Genetic; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013954:Thyroglobulin / Q000276:immunology*; D013967:Thyroiditis, Autoimmune / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology
chemical_list: D013954:Thyroglobulin