Induced sensitization of tumor stroma leads to eradication of established cancer by T cells.
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.
Zhang
Bin
B
Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. bzhang2@uchicago.edu
Bowerman
Natalie A
NA
Salama
Joseph K
JK
Schmidt
Hank
H
Spiotto
Michael T
MT
Schietinger
Andrea
A
Yu
Ping
P
Fu
Yang-Xin
YX
Weichselbaum
Ralph R
RR
Rowley
Donald A
DA
Kranz
David M
DM
Schreiber
Hans
H
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
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D011948:Receptors, Antigen, T-Cell; D003841:Deoxycytidine; D000093542:Gemcitabine