Stimulation through very late antigen-4 and -5 improves the multifunctionality and memory formation of CD8⁺ T cells.
T cells express multiple integrin molecules. The significance of signaling through these molecules on acquisition of T-cell effector functions and memory formation capacity remains largely unknown. Moreover, the impact of stimulation through these signals on the generation of T cells for adoptive immunotherapy has not been elucidated. In this study, using a recombinant fragment of fibronectin, CH-296, we demonstrated that stimulation via very late Ag (VLA)-4 and VLA-5 in human and BALB/c mouse CD8(+) T cells, in combination with TCR stimulation, enhances effector multifunctionality and in vivo memory formation. Using TCR-transgenic mouse-derived CD8(+) T cells expressing TCR specific for the syngeneic CMS5 fibrosarcoma-derived tumor Ag, we showed that stimulation by CH-296 improved the ability of tumor-specific CD8(+) T cells to inhibit CMS5 tumor growth when adoptively transferred into hosts with progressing tumors. Improved antitumor effects were associated with decreased infiltration of Foxp3(+) CD4(+) Treg cells in tumors. These results suggest that stimulation via VLA-4 and VLA-5 modulates the qualities of effector T cells and could potentially increase the efficacy of adoptive therapy against cancer.
Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Japan; Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Hayato
H
Hosoi
Hiroaki
H
Ikeda
Naoko
N
Imai
Chisaki
C
Amaike
Linan
L
Wang
Yuki
Y
Orito
Makiko
M
Yamane
Hiroaki
H
Ueno
Mitsuko
M
Ideno
Ikuei
I
Nukaya
Tatsuji
T
Enoki
Junichi
J
Mineno
Kazutoh
K
Takesako
Satoshi
S
Hirano
Hiroshi
H
Shiku
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes; D045744:Cell Line, Tumor; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007156:Immunologic Memory; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology*; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D000951:Antigens, Neoplasm; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1
CD8+ T cells; Integrins; Multifunctionality; Tumor immunology; Very late antigen (VLA)