A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model.
Her-2/neu is a well-characterized tumor-associated antigen overexpressed in human carcinomas such as breast cancer. Because Her-2/neu is a self-antigen with poor immunogenicity due to immunologic tolerance, active immunotherapy targeting Her-2/neu should incorporate methods to overcome immunologic tolerance to self-proteins. In this study, we developed a tolerogenic tumor model in mice using mouse Her-2/neu as self-antigen and investigated whether genetic vaccination with DNA plasmid and/or adenoviral vector expressing the extracellular and transmembrane domain of syngeneic mouse Her-2/neu or xenogenic human Her-2/neu could induce mouse Her-2/neu-specific CTL responses. Interestingly, adenoviral vectors expressing xenogenic human Her-2/neu (AdhHM) proved capable of breaking immune tolerance and of thereby inducing self-reactive CTL and antibodies, but not to the degree required to induce therapeutic antitumor immunity. In attempting to generate therapeutic antitumor immunity against established tumors, we adopted several approaches. Treatment with agonistic anti-glucocorticoid-induced TNFR family-related receptor (GITR) antibody plus AdhHM immunization significantly increased self-reactive CTL responses, and alpha-galactosylceramide (alphaGalCer)-loaded dendritic cells (DC) transduced with AdhHM were shown to break self-tolerance in a tolerogenic murine tumor model. Furthermore, gemcitabine treatment together with either AdhHM plus agonistic anti-GITR antibody administration or alphaGalCer-loaded DC transduced with AdhHM showed potent therapeutic antitumor immunity and perfect protection against preexisting tumors. Gemcitabine treatment attenuated the tumor-suppressive environment by eliminating CD11b(+)/Gr-1(+) myeloid-derived suppressor cells. When combined with immunotherapies, gemcitabine offers a promising strategy for the Ag-specific treatment of human cancer.
Ko
Hyun-Jeong
HJ
Laboratory of Immunology, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Kim
Yeon-Jeong
YJ
Kim
Yun-Sun
YS
Chang
Woo-Sung
WS
Ko
Sung-Youl
SY
Chang
Sun-Young
SY
Sakaguchi
Shimon
S
Kang
Chang-Yuil
CY
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000276:immunology; D005822:Genetic Vectors / Q000008:administration & dosage; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007114:Immunization; D007167:Immunotherapy; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory; D043823:Taxoids / Q000008:administration & dosage; D014162:Transfection; D019444:Vaccines, DNA / Q000008:administration & dosage; D000093542:Gemcitabine
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D003520:Cyclophosphamide; D003841:Deoxycytidine; D000077143:Docetaxel; D004317:Doxorubicin; D005699:Galactosylceramides; D053450:Glucocorticoid-Induced TNFR-Related Protein; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D043823:Taxoids; D019444:Vaccines, DNA; D000093542:Gemcitabine; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C106544:Tnfrsf18 protein, mouse