Vaccine-stimulated, adoptively transferred CD8+ T cells traffic indiscriminately and ubiquitously while mediating specific tumor destruction.
It has been suggested that antitumor T cells specifically traffic to the tumor site, where they effect tumor destruction. To test whether tumor-reactive CD8(+) T cells specifically home to tumor, we assessed the trafficking of gp100-specific pmel-1 cells to large, vascularized tumors that express or do not express the target Ag. Activation of tumor-specific CD8(+) pmel-1 T cells with IL-2 and vaccination with an altered peptide ligand caused regression of gp100-positive tumors (B16), but not gp100-negative tumors (methylcholanthrene 205), implanted on opposing flanks of the same mouse. Surprisingly, we found approximately equal and very large numbers of pmel-1 T cells (>25% of all lymphocytes) infiltrating both Ag-positive and Ag-negative tumors. We also found evidence of massive infiltration and proliferation of activated antitumor pmel-1 cells in a variety of peripheral tissues, including lymph nodes, liver, spleen, and lungs, but not peripheral blood. Most importantly, evidence for T cell function, as measured by production of IFN-gamma, release of perforin, and activation of caspase-3 in target cells, was confined to Ag-expressing tumor. We thus conclude that CD8(+) T cell-mediated destruction of tumor is the result of specific T cell triggering at the tumor site. The ability to induce ubiquitous homing and specific tumor destruction may be important in the case of noninflammatory metastatic tumor foci.
Palmer
Douglas C
DC
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. palmerd@mail.nih.gov
Balasubramaniam
Sanjeeve
S
Hanada
Ken-Ichi
K
Wrzesinski
Claudia
C
Yu
Zhiya
Z
Farid
Shahram
S
Theoret
Marc R
MR
Hwang
Leroy N
LN
Klebanoff
Christopher A
CA
Gattinoni
Luca
L
Goldstein
Allan L
AL
Yang
James C
JC
Restifo
Nicholas P
NP
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005354:Fibrosarcoma / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D016219:Immunotherapy, Adoptive / Q000379:methods; D008213:Lymphocyte Activation / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation*; D008546:Melanoma, Experimental / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D009368:Neoplasm Transplantation / Q000276:immunology / Q000379:methods / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D058951:gp100 Melanoma Antigen
D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen