High frequencies of less differentiated and more proliferative WT1-specific CD8+ T cells in bone marrow in tumor-bearing patients: an important role of bone marrow as a secondary lymphoid organ.
In tumor-bearing patients, tumor-associated antigen (TAA)-specific CTLs are spontaneously induced as a result of immune response to TAAs and play an important role in anti-tumor immunity. Wilms' tumor gene 1 (WT1) is overexpressed in various types of tumor and WT1 protein is a promising pan-TAA because of its high immunogenicity. In this study, to clarify the immune response to the WT1 antigen, WT1-specific CD8(+) T cells that were spontaneously induced in patients with solid tumor were comparatively analyzed in both bone marrow (BM) and peripheral blood (PB). WT1-specific CD8(+) T cells more frequently existed in BM than in PB, whereas frequencies of naïve (CCR7(+) CD45RA(+)), central memory (CCR7(+) CD45RA-), effector-memory (CCR7- CD45RA(-)), and effector (CCR7- CD45RA(+)) subsets were not significantly different between BM and PB. However, analysis of these subsets for the expression of CD57 and CD28, which were associated with differentiation, revealed that effector-memory and effector subsets of the WT1-specific CD8(+) T cells in BM had less differentiated phenotypes and more proliferative potential than those in PB. Furthermore, CD107a/b functional assay for WT1 peptide-specific cytotoxic potential and carboxyfluorescein diacetate succinimidyl ester dilution assay for WT1 peptide-specific proliferation also showed that WT1-specific CD8(+) T cells in BM were less cytotoxic and more proliferative in response to WT1 peptide than those in PB. These results implied that BM played an important role as a secondary lymphoid organ in tumor-bearing patients. Preferential residence of WT1-specific CD8(+) T cells in BM could be, at least in part, explained by higher expression of chemokine receptor CCR5, whose ligand was expressed on BM fibroblasts on the WT1-specific CD8(+) T cells in BM, compared to those in PB. These results should provide us with an insight into WT1-specific immune response in tumor-bearing patients and give us an idea of enhancement of clinical response in WT1 protein-targeted immunotherapy.
Department of Respiratory Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Ayako
A
Murao
Yoshihiro
Y
Oka
Akihiro
A
Tsuboi
Olga A
OA
Elisseeva
Yukie
Y
Tanaka-Harada
Fumihiro
F
Fujiki
Hiroko
H
Nakajima
Sumiyuki
S
Nishida
Naoki
N
Hosen
Toshiaki
T
Shirakata
Nobuyuki
N
Hashimoto
Akira
A
Myoui
Takafumi
T
Ueda
Yoshito
Y
Takeda
Tadashi
T
Osaki
Takayuki
T
Enomoto
Hideki
H
Yoshikawa
Tadashi
T
Kimura
Yusuke
Y
Oji
Ichiro
I
Kawase
Haruo
H
Sugiyama
D000293:Adolescent; D000368:Aged; D001853:Bone Marrow / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D017493:Leukocyte Common Antigens / Q000032:analysis / Q000276:immunology; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology*; D025721:WT1 Proteins / Q000502:physiology*
D025721:WT1 Proteins; D017493:Leukocyte Common Antigens