Autoimmune thyroiditis as an indicator of autoimmune sequelae during cancer immunotherapy.
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.
Kong
Yi-chi M
YC
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. ykong@med.wayne.edu
Jacob
Jennifer B
JB
Flynn
Jeffrey C
JC
Elliott
Bruce E
BE
Wei
Wei-Zen
WZ
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
D013954:Thyroglobulin