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.

Autor: Murao, Ayako, Oka, Yoshihiro, Tsuboi, Akihiro, Elisseeva, Olga A., Tanaka-Harada, Yukie, Fujiki, Fumihiro, Nakajima, Hiroko, Nishida, Sumiyuki, Hosen, Naoki, Shirakata, Toshiaki, Hashimoto, Nobuyuki, Myoui, Akira, Ueda, Takafumi, Takeda, Yoshito, Osaki, Tadashi, Enomoto, Takayuki, Yoshikawa, Hideki, Kimura, Tadashi, Oji, Yusuke, Kawase, Ichiro
Zdroj: Cancer Science; Apr2010, Vol. 101 Issue 4, p848-854, 7p, 1 Chart, 6 Graphs
Abstrakt: 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. ( Cancer Sci 2010; 101: 848–854) [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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