CONSTITUTIVE UP-REGULATION OF INTEGRIN-MEDIATED ADHESION OF TUMOR-INFILTRATING LYMPHOCYTES TO OSTEOBLASTS AND BONE-MARROW-DERIVED STROMAL CELLS

Tumor-reactive T cells, known as tumor-infiltrating lymphocyte(TIL)s a re known to infiltrate various tumors. Although TILs exert cytotoxic a ctivities against tumor cells, only a small percentage of tumors usual ly contain TILs that specifically react to tumor antigens, Because the exact role of these lymphocytes is unclear, we investigated the mecha nisms of migration and adhesion of TILs to bone metastatic tumors, par ticularly 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 fo und in the supporting tissue stroma between the bone and tumor mass. C ultured TILs (obtained from breast tumors) adhered spontaneously to os teoblasts and BMSCs (obtained from patients with osteoarthritis) witho ut exogenous stimulation. Adhesion was further enhanced by chemokines macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, TILs hig hly expressed activation antigens CD25 and CD69, A spontaneous activat ion of an integrin, lymphocyte function-associated antigen-1 (LFA-1), was also detected on TILs, TILs produced high concentrations of MIP-1 alpha and MIP-1 beta 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 produ ction of osteoclastogen interleukin 6 by the latter cells. Our results indicate that integrins on TILs are activated in an autocrine manner by MIP-1 alpha and MIP-1 beta, and that treatment with the chemokines increases the binding of TILs on osteoblasts and stromal cells via a m echanism involving intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as targets for the integrin, Our data also indica ted that interactions between TILs and osteoblasts/stromal cells lead to the secretion by the latter of the osteoclastogenic cytokine interl eukin 6.