title: Combinational Immunotherapy with Allo-DRibble Vaccines and Anti-OX40 Co-Stimulation Leads to Generation of Cross-Reactive Effector T Cells and Tumor Regression.
abstract: It is well-known that vaccines comprising of irradiated whole tumor cells or tumor-derived heat shock proteins can generate tumor-specific immune responses. In contrast, we showed recently that vaccines composed of autophagosomes (DRibbles) derived from syngeneic sarcomas could induce cross-reactive T-cell responses and cross-protection against the tumor. This unusual property of DRibbles was related to the selective recruitment of defective ribosomal products (DRiPs) and other short-lived proteins (SLiPs) into autophagosomes via sequestosome (SQSTM1, p62) mediated association of ubiquitinated SLiPs to the autophagy gene product LC3. Here, we extend our observations to mammary carcinomas from mice of different genetic background. We demonstrated that combined of intranodal administration of autologous or allogeneic DRibbles together with anti-OX40 antibody led to robust proliferation, expansion, and differentiation of memory and effector T cells. We also showed that SLiPs is an excellent source of antigen for cross-priming of CD8+T-cells that recognize shared tumor antigens in the context of host MHC class I molecules. Thus, our results provide a strong basis for novel clinical trials that combine allogeneic "off-the-shelf" DRibble vaccines together with antibodies against co-stimulatory molecules.
authors.affiliation: School of Medicine, Southeast University, Nanjing, PR China.|Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Yu
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Morris
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Weinberg
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fox
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Urba
authors.affiliation: School of Medicine, Southeast University, Nanjing, PR China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Hu
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D000071182:Autophagosomes / Q000276:immunology; D001343:Autophagy / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D000071456:Sequestosome-1 Protein / Q000276:immunology
chemical_list: D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C406562:OX40Ig; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse