NK CELL INFILTRATION INTO LUNG, LIVER, AND SUBCUTANEOUS B16 MELANOMA IS MEDIATED BY VCAM-1 VLA-4 INTERACTION/

The mechanisms that regulate the adhesion and migration of NK cells to and across endothelium have been studied under nonflow conditions; ho wever, the involvement of these processes in vivo is poorly understood . The present studies investigated the potential vascular adhesion lig and interactions that determine the in vivo recruitment of NK cells to pulmonary and hepatic parenchyma, and s.c. tumor after treatment of m ice with biologic response modifiers. Seventy-two hours after a single injection of the cytokine-inducing agent poly-L-lysine stabilized in carboxylmethyl cellulose (poly-ICLC), pulmonary NK cell lytic activity and N-alpha-carbobenzoxy-L-lysine thiobenzyl ester (BLT)-esterase wer e augmented 29- and 14-fold, respectively, and the number of lung-asso ciated NK cells was increased from 2.3 x 10(5) to 7.4 x 10(5). Similar fold increases in NK cell number and activity were observed in the li ver and s.c. B16 melanoma after poly-ICLC injection or in the lungs an d liver of mice treated with IL-2. Concomitant treatment of mice with alpha-VCAM-1 or alpha-VLA-4 mAb, but not alpha-ICAM-1 or alpha-LFA-1, abrogated the poly-ICLC and IL-2-induced increase in organ-associated NK activity and percentage of tumor-associated NK cells, resulted in a 61 to 76% decrease in pulmonary and hepatic NK cell number, and was i ndependent of T and/or B cells. The decrease in NK cell number in orga n parenchyma and tumor lesions was correlated to an increase in the nu mber of NK cells in peripheral blood, but not bone marrow. These resul ts demonstrate that VCAM-1/VLA-4 interaction is critically involved in the infiltration of newly recruited NK cells into lung, liver, and pr ogressively growing tumor after mobilization from the bone marrow.