Tumor-induced L-selectinhigh suppressor T cells mediate potent effector T cell blockade and cause failure of otherwise curative adoptive immunotherapy.
Tumor-specific effector T cells (T(E)) are naturally sensitized within the L-selectin(low) (CD62L(low)) fraction of tumor-draining lymph nodes (TDLN). Whether isolated from day 9 (D9) or day 12 (D12) TDLN, 5 million L-selectin(low) T(E) could be culture activated and adoptively transferred to achieve complete rejection of established intradermal, pulmonary, and brain tumors. Surprisingly, although 25 million unfractionated T cells from D9 TDLN were equally effective, even 100 million unfractionated T cells from D12 TDLN seldom prevented lethal intradermal tumor progression, despite a pronounced therapeutic excess of T(E). This highly reproducible treatment failure was due to cotransfer of tumor-induced, L-selectin(high) suppressor T cells (T(S)) which were also present in D12 TDLN. In contrast, D9 TDLN and normal spleens lacked L-selectin(high) T(S). Only those L-selectin(high) D12 TDLN T cells that down-regulated L-selectin during culture activation were suppressive in vivo and in vitro, and, like L-selectin(low) T(E), trafficked promptly into tumors following i.v. administration. This is the first demonstration that adoptive immunotherapy can fail as a direct result of passenger T(S) that share certain phenotypic and trafficking features of T(E), even when otherwise curative doses of T(E) have been administered. Furthermore, in contrast to recently described CD4(+)CD25(+) T(S) and plasmacytoid dendritic cell-activated T(S), tumor-induced L-selectin(high) T(S) prevent tumor rejection via blockade of sensitized, activated T(E) rather than via afferent blockade.
Peng
Liaomin
L
Center for Surgery Research, Cleveland Clinic Foundation, and Lerner Research Institute, OH 44195, USA.
Kjaergäard
Jørgen
J
Plautz
Gregory E
GE
Awad
Mohamed
M
Drazba
Judith A
JA
Shu
Suyu
S
Cohen
Peter A
PA
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D002469:Cell Separation; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D006649:Histocompatibility Antigens / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007271:Injections, Intradermal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019041:L-Selectin / Q000096:biosynthesis* / Q000502:physiology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D017211:Treatment Failure; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D006649:Histocompatibility Antigens; C029237:tumor-associated transplantation antigen; D019041:L-Selectin; D007371:Interferon-gamma