title: Induced sensitization of tumor stroma leads to eradication of established cancer by T cells.
abstract: Targeting cancer cells, as well as the nonmalignant stromal cells cross-presenting the tumor antigen (Ag), can lead to the complete destruction of well-established solid tumors by adoptively transferred Ag-specific cytotoxic T lymphocytes (CTLs). If, however, cancer cells express only low levels of the Ag, then stromal cells are not destroyed, and the tumor escapes as Ag loss variants. We show that treating well-established tumors expressing low levels of Ag with local irradiation or a chemotherapeutic drug causes sufficient release of Ag to sensitize stromal cells for destruction by CTLs. This was shown directly using high affinity T cell receptor tetramers for visualizing the transient appearance of tumor-specific peptide-MHC complexes on stromal cells. Maximum loading of tumor stroma with cancer Ag occurred 2 d after treatment and coincided with the optimal time for T cell transfer. Under these conditions, tumor rejection was complete. These findings may set the stage for developing rational clinical protocols for combining irradiation or chemotherapy with CTL therapy.
authors.affiliation: Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. bzhang2@uchicago.edu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bowerman
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Salama
authors.forename: Hank
authors.initials: H
authors.lastname: Schmidt
authors.forename: Michael T
authors.initials: MT
authors.lastname: Spiotto
authors.forename: Andrea
authors.initials: A
authors.lastname: Schietinger
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Donald A
authors.initials: DA
authors.lastname: Rowley
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
authors.forename: Hans
authors.initials: H
authors.lastname: Schreiber
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D007114:Immunization; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000532:radiotherapy; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000093542:Gemcitabine
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D011948:Receptors, Antigen, T-Cell; D003841:Deoxycytidine; D000093542:Gemcitabine