TUMOR ENDOTHELIUM SELECTIVELY SUPPORTS BINDING OF IL-2-PROPAGATED TUMOR-INFILTRATING LYMPHOCYTES

Entrance of activated T cells into the tumor after adoptive transfer i s a prerequisite for the efficacy of this form of immunotherapy. Becau se lymphocyte binding to vascular endothelium is the critical step in which lymphocyte extravasation into the tissue is controlled, we compa red adhesion of tumor-infiltrating lymphocytes (TIL) to endothelial ce lls in tumors, peripheral lymph nodes, mucosa-associated lymphatic tis sues, and inflamed synovium. Simultaneously, expression of the known h oming-associated Ags both on TIL and tumor vasculature was analyzed. A ll TIL strongly expressed alpha 4-integrins, LFA-1 and CD44, whereas o nly a low level of L-selectin expression was detected. Tumor vasculatu re showed signs of activation in each patient on the basis of elevated levels of intercellular adhesion molecule-1, E-selectin, vascular cel l adhesion molecule-1, and/or peripheral lymph node addressin (PNAd). TIL showed significantly enhanced binding to tumor vasculature in comp arison with other endothelial specificities. Increased binding was not markedly due to up-regulation of the inflammation-induced endothelial cell adhesion molecules in tumors, because binding to inflamed synovi um that expressed the same adhesion molecules was not enhanced. In sum mary, TIL show preferential binding to tumor vasculature and the bindi ng is partially mediated by currently unknown mechanisms. In vitro ana lysis of endothelial cell binding properties may help to identify thos e TIL populations that will have the best potential to home back to tu mor tissue after adoptive transfer.