Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants.
Defects in major histocompatibility complex (MHC) class I-restricted antigen presentation are frequently observed in human cancers and result in escape of tumors from cytotoxic T lymphocyte (CTL) immune surveillance in mice. Here, we show the existence of a unique category of CTLs that can prevent this escape. The CTLs target an alternative repertoire of peptide epitopes that emerge in MHC class I at the surface of cells with impaired function of transporter associated with antigen processing (TAP), tapasin or the proteasome. These peptides, although derived from self antigens such as the commonly expressed Lass5 protein (also known as Trh4), are not presented by normal cells. This explains why they act as immunogenic neoantigens. The newly discovered epitopes can be exploited for immune intervention against processing-deficient tumors through adoptive T-cell transfer or peptide vaccination.
van Hall
Thorbald
T
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. t.van_hall@lumc.nl
Wolpert
Elisabeth Z
EZ
van Veelen
Peter
P
Laban
Sandra
S
van der Veer
Michael
M
Roseboom
Marjet
M
Bres
Sandra
S
Grufman
Per
P
de Ru
Arnoud
A
Meiring
Hugo
H
de Jong
Ad
A
Franken
Kees
K
Teixeira
Antoinette
A
Valentijn
Rob
R
Drijfhout
Jan Wouter
JW
Koning
Frits
F
Camps
Marcel
M
Ossendorp
Ferry
F
Kärre
Klas
K
Ljunggren
Hans-Gustaf
HG
Melief
Cornelis J M
CJ
Offringa
Rienk
R
D000818:Animals; D017951:Antigen Presentation; D017920:Antiporters / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D000939:Epitopes; D018390:Gene Targeting; D005805:Genes, MHC Class I; D014644:Genetic Variation; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007136:Immunoglobulins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007157:Immunologic Surveillance; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape; D014614:Vaccines, Synthetic / Q000627:therapeutic use
D017920:Antiporters; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D014614:Vaccines, Synthetic; C107762:tapasin