title: Transfer of Allogeneic CD4+ T Cells Rescues CD8+ T Cells in Anti-PD-L1-Resistant Tumors Leading to Tumor Eradication.
abstract: Adoptively transferred CD8+T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T-cell-mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule Kbneeded for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8+T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the "exhaustion" markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4+T cells restored the numbers of circulating Ag-specific CD8+T cells and their intratumoral function, resulting in tumor eradication. These CD4+T cells had no antitumor effects in the absence of CD8+T cells and recognized the alloantigen cross-presented on tumor stroma. CD4+T cells might also be effective in cancer patients when PD-1/PD-L1 blockade does not rescue intratumoral CD8+T-cell function and tumors persist. Cancer Immunol Res; 5(2); 127-36. ©2017 AACR.
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois. aarina@bsd.uchicago.edu.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arina
authors.affiliation: Department of Health Studies, The University of Chicago, Chicago, Illinois.
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois.
authors.forename: Eva
authors.initials: E
authors.lastname: Galka
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Karin
authors.initials: K
authors.lastname: Schreiber
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Hans
authors.initials: H
authors.lastname: Schreiber
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D016207:Cytokines; D000949:Histocompatibility Antigens Class II