Helper-independent, L-selectinlow CD8+ T cells with broad anti-tumor efficacy are naturally sensitized during tumor progression.
We recently reported that the CD4(+) T cell subset with low L-selectin expression (CD62L(low)) in tumor-draining lymph nodes (TDLN) can be culture activated and adoptively transferred to eradicate established pulmonary and intracranial tumors in syngeneic mice, even without coadministration of IL-2. We have extended these studies to characterize the small subset of L-selectin(low) CD8(+) T cells naturally present in TDLN of mice bearing weakly immunogenic tumors. Isolated L-selectin(low) CD8(+) T cells displayed the functional phenotype of helper-independent T cells, and when adoptively transferred could consistently eradicate, like L-selectin(low) CD4(+) T cells, both established pulmonary and intracranial tumors without coadministration of exogenous IL-2. Whereas adoptively transferred L-selectin(low) CD4(+) T cells were more potent on a cell number basis for eradicating 3-day intracranial and s.c. tumors, L-selectin(low) CD8(+) T cells were more potent against advanced (10-day) pulmonary metastases. Although the presence of CD4(+) T cells enhanced generation of L-selectin(low) CD8(+) effector T cells, the latter could also be obtained from CD4 knockout mice or normal mice in vivo depleted of CD4(+) T cells before tumor sensitization. Culture-activated L-selectin(low) CD8(+) T cells did not lyse relevant tumor targets in vitro, but secreted IFN-gamma and GM-CSF when specifically stimulated with relevant tumor preparations. These data indicate that even without specific vaccine maneuvers, progressive tumor growth leads to independent sensitization of both CD4(+) and CD8(+) anti-tumor T cells in TDLN, phenotypically L-selectin(low) at the time of harvest, each of which requires only culture activation to unmask highly potent stand-alone effector function.
Peng
L
L
Center for Surgery Research and Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Kjaergaard
J
J
Plautz
G E
GE
Weng
D E
DE
Shu
S
S
Cohen
P A
PA
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D002469:Cell Separation; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D018450:Disease Progression; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D016219:Immunotherapy, Adoptive / Q000379:methods; D007279:Injections, Subcutaneous; D019041:L-Selectin / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000637:transplantation
D019041:L-Selectin