Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells

Y Tanaka, S Mine, T Hanagiri, T Hiraga, I Morimoto, C G Figdor, Y van Kooyk, H Ozawa, T Nakamura, K Yasumoto, S Eto

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Tumor-reactive T cells, known as tumor-infiltrating lymphocyte(TIL)s are known to infiltrate various tumors. Although TILs exert cytotoxic activities against tumor cells, only a small percentage of tumors usually contain TILs that specifically react to tumor antigens. Because the exact role of these lymphocytes is unclear, we investigated the mechanisms of migration and adhesion of TILs to bone metastatic tumors, particularly to osteoblasts and bone marrow-derived stromal cell(BMSC)s. Histopathological examination showed that most TILs in secondary bone metastatic tumors (from primary tumors in the lung or breast) were found in the supporting tissue stroma between the bone and tumor mass. Cultured TILs (obtained from breast tumors) adhered spontaneously to osteoblasts and BMSCs (obtained from patients with osteoarthritis) without exogenous stimulation. Adhesion was further enhanced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. TILs highly expressed activation antigens CD25 and CD69. A spontaneous activation of an integrin, lymphocyte function-associated antigen-1 (LFA-1), was also detected on TILs. TILs produced high concentrations of MIP-1alpha and MIP-1beta and spontaneous polymerization of cytoskeletal F-actin was observed in these cells. Adhesion of TILs to osteoblasts and BMSCs via LFA-1 and very late antigen-4 was associated with the production of osteoclastogen interleukin 6 by the latter cells. Our results indicate that integrins on TILs are activated in an autocrine manner by MIP-1alpha and MIP-1beta, and that treatment with the chemokines increases the binding of TILs on osteoblasts and stromal cells via a mechanism involving intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as targets for the integrin. Our data also indicated that interactions between TILs and osteoblasts/stromal cells lead to the secretion by the latter of the osteoclastogenic cytokine interleukin 6.

Original languageEnglish
Pages (from-to)4138-45
Number of pages8
JournalCancer Research
Volume58
Issue number18
Publication statusPublished - 15 Sep 1998

Cite this

Tanaka, Y., Mine, S., Hanagiri, T., Hiraga, T., Morimoto, I., Figdor, C. G., ... Eto, S. (1998). Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells. Cancer Research, 58(18), 4138-45.
Tanaka, Y ; Mine, S ; Hanagiri, T ; Hiraga, T ; Morimoto, I ; Figdor, C G ; van Kooyk, Y ; Ozawa, H ; Nakamura, T ; Yasumoto, K ; Eto, S. / Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells. In: Cancer Research. 1998 ; Vol. 58, No. 18. pp. 4138-45.
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title = "Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells",
abstract = "Tumor-reactive T cells, known as tumor-infiltrating lymphocyte(TIL)s are known to infiltrate various tumors. Although TILs exert cytotoxic activities against tumor cells, only a small percentage of tumors usually contain TILs that specifically react to tumor antigens. Because the exact role of these lymphocytes is unclear, we investigated the mechanisms of migration and adhesion of TILs to bone metastatic tumors, particularly to osteoblasts and bone marrow-derived stromal cell(BMSC)s. Histopathological examination showed that most TILs in secondary bone metastatic tumors (from primary tumors in the lung or breast) were found in the supporting tissue stroma between the bone and tumor mass. Cultured TILs (obtained from breast tumors) adhered spontaneously to osteoblasts and BMSCs (obtained from patients with osteoarthritis) without exogenous stimulation. Adhesion was further enhanced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. TILs highly expressed activation antigens CD25 and CD69. A spontaneous activation of an integrin, lymphocyte function-associated antigen-1 (LFA-1), was also detected on TILs. TILs produced high concentrations of MIP-1alpha and MIP-1beta and spontaneous polymerization of cytoskeletal F-actin was observed in these cells. Adhesion of TILs to osteoblasts and BMSCs via LFA-1 and very late antigen-4 was associated with the production of osteoclastogen interleukin 6 by the latter cells. Our results indicate that integrins on TILs are activated in an autocrine manner by MIP-1alpha and MIP-1beta, and that treatment with the chemokines increases the binding of TILs on osteoblasts and stromal cells via a mechanism involving intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as targets for the integrin. Our data also indicated that interactions between TILs and osteoblasts/stromal cells lead to the secretion by the latter of the osteoclastogenic cytokine interleukin 6.",
keywords = "Actins/metabolism, Antigens, CD/metabolism, Antigens, Differentiation, T-Lymphocyte/metabolism, Bone Marrow/immunology, Bone Neoplasms/immunology, Cell Adhesion/physiology, Cell Movement/physiology, Chemokine CCL3, Chemokine CCL4, Female, Humans, Immunotherapy, Adoptive/methods, Integrins/metabolism, Intercellular Adhesion Molecule-1/metabolism, Interleukin-6/metabolism, Lectins, C-Type, Lymphocyte Function-Associated Antigen-1/metabolism, Lymphocytes, Tumor-Infiltrating/metabolism, Macrophage Inflammatory Proteins/metabolism, Osteoblasts/immunology, Polymers, Receptors, Interleukin-2/metabolism, Stromal Cells/metabolism, Up-Regulation, Vascular Cell Adhesion Molecule-1/metabolism",
author = "Y Tanaka and S Mine and T Hanagiri and T Hiraga and I Morimoto and Figdor, {C G} and {van Kooyk}, Y and H Ozawa and T Nakamura and K Yasumoto and S Eto",
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Tanaka, Y, Mine, S, Hanagiri, T, Hiraga, T, Morimoto, I, Figdor, CG, van Kooyk, Y, Ozawa, H, Nakamura, T, Yasumoto, K & Eto, S 1998, 'Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells' Cancer Research, vol. 58, no. 18, pp. 4138-45.

Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells. / Tanaka, Y; Mine, S; Hanagiri, T; Hiraga, T; Morimoto, I; Figdor, C G; van Kooyk, Y; Ozawa, H; Nakamura, T; Yasumoto, K; Eto, S.

In: Cancer Research, Vol. 58, No. 18, 15.09.1998, p. 4138-45.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells

AU - Tanaka, Y

AU - Mine, S

AU - Hanagiri, T

AU - Hiraga, T

AU - Morimoto, I

AU - Figdor, C G

AU - van Kooyk, Y

AU - Ozawa, H

AU - Nakamura, T

AU - Yasumoto, K

AU - Eto, S

PY - 1998/9/15

Y1 - 1998/9/15

N2 - Tumor-reactive T cells, known as tumor-infiltrating lymphocyte(TIL)s are known to infiltrate various tumors. Although TILs exert cytotoxic activities against tumor cells, only a small percentage of tumors usually contain TILs that specifically react to tumor antigens. Because the exact role of these lymphocytes is unclear, we investigated the mechanisms of migration and adhesion of TILs to bone metastatic tumors, particularly to osteoblasts and bone marrow-derived stromal cell(BMSC)s. Histopathological examination showed that most TILs in secondary bone metastatic tumors (from primary tumors in the lung or breast) were found in the supporting tissue stroma between the bone and tumor mass. Cultured TILs (obtained from breast tumors) adhered spontaneously to osteoblasts and BMSCs (obtained from patients with osteoarthritis) without exogenous stimulation. Adhesion was further enhanced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. TILs highly expressed activation antigens CD25 and CD69. A spontaneous activation of an integrin, lymphocyte function-associated antigen-1 (LFA-1), was also detected on TILs. TILs produced high concentrations of MIP-1alpha and MIP-1beta and spontaneous polymerization of cytoskeletal F-actin was observed in these cells. Adhesion of TILs to osteoblasts and BMSCs via LFA-1 and very late antigen-4 was associated with the production of osteoclastogen interleukin 6 by the latter cells. Our results indicate that integrins on TILs are activated in an autocrine manner by MIP-1alpha and MIP-1beta, and that treatment with the chemokines increases the binding of TILs on osteoblasts and stromal cells via a mechanism involving intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as targets for the integrin. Our data also indicated that interactions between TILs and osteoblasts/stromal cells lead to the secretion by the latter of the osteoclastogenic cytokine interleukin 6.

AB - Tumor-reactive T cells, known as tumor-infiltrating lymphocyte(TIL)s are known to infiltrate various tumors. Although TILs exert cytotoxic activities against tumor cells, only a small percentage of tumors usually contain TILs that specifically react to tumor antigens. Because the exact role of these lymphocytes is unclear, we investigated the mechanisms of migration and adhesion of TILs to bone metastatic tumors, particularly to osteoblasts and bone marrow-derived stromal cell(BMSC)s. Histopathological examination showed that most TILs in secondary bone metastatic tumors (from primary tumors in the lung or breast) were found in the supporting tissue stroma between the bone and tumor mass. Cultured TILs (obtained from breast tumors) adhered spontaneously to osteoblasts and BMSCs (obtained from patients with osteoarthritis) without exogenous stimulation. Adhesion was further enhanced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. TILs highly expressed activation antigens CD25 and CD69. A spontaneous activation of an integrin, lymphocyte function-associated antigen-1 (LFA-1), was also detected on TILs. TILs produced high concentrations of MIP-1alpha and MIP-1beta and spontaneous polymerization of cytoskeletal F-actin was observed in these cells. Adhesion of TILs to osteoblasts and BMSCs via LFA-1 and very late antigen-4 was associated with the production of osteoclastogen interleukin 6 by the latter cells. Our results indicate that integrins on TILs are activated in an autocrine manner by MIP-1alpha and MIP-1beta, and that treatment with the chemokines increases the binding of TILs on osteoblasts and stromal cells via a mechanism involving intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as targets for the integrin. Our data also indicated that interactions between TILs and osteoblasts/stromal cells lead to the secretion by the latter of the osteoclastogenic cytokine interleukin 6.

KW - Actins/metabolism

KW - Antigens, CD/metabolism

KW - Antigens, Differentiation, T-Lymphocyte/metabolism

KW - Bone Marrow/immunology

KW - Bone Neoplasms/immunology

KW - Cell Adhesion/physiology

KW - Cell Movement/physiology

KW - Chemokine CCL3

KW - Chemokine CCL4

KW - Female

KW - Humans

KW - Immunotherapy, Adoptive/methods

KW - Integrins/metabolism

KW - Intercellular Adhesion Molecule-1/metabolism

KW - Interleukin-6/metabolism

KW - Lectins, C-Type

KW - Lymphocyte Function-Associated Antigen-1/metabolism

KW - Lymphocytes, Tumor-Infiltrating/metabolism

KW - Macrophage Inflammatory Proteins/metabolism

KW - Osteoblasts/immunology

KW - Polymers

KW - Receptors, Interleukin-2/metabolism

KW - Stromal Cells/metabolism

KW - Up-Regulation

KW - Vascular Cell Adhesion Molecule-1/metabolism

M3 - Article

VL - 58

SP - 4138

EP - 4145

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 18

ER -