IMPAIRMENT OF LYMPHOCYTE LOCOMOTION IN THE TUMOR MICROENVIRONMENT ANDTHE EFFECT OF SYSTEMIC IMMUNOTHERAPY WITH LIPOSOME-ENCAPSULATED MURAMYL-TRIPEPTIDE-PHOSPHATIDYLETHANOLAMINE

The ability of the lymphocytes to move through the interstitium is obl igatory to the immune response. We previously showed that tumor-infilt rating lymphocytes (TIL) from human melanoma and renal cell carcinoma demonstrate a dramatic decrease in their spontaneous locomotion throug h three-dimensional collagen gel when compared with peripheral blood l ymphocytes (PBL) and lymph node lymphocytes. To determine if this decr ease is caused by contact with tumor cells, or mediated through certai n diffusible factors, we examined the effects of autologous tumor cell s on the locomotion of PBL in a model system where tumor cells were se parated from lymphocytes by a 3-mm layer of gelled collagen. After 21- 22 h incubation in chamber slides, locomotion distances were assessed in the presence and absence of tumor and normal cells. In the presence of tumor cells, PBL from 14 of 18 patients displayed substantial (466 .5+/-2.7 mu m compared to control 568.9+/-10.9 mu m, P<0.001) loss of motility. Inhibition was more prominent in melanoma patients than in r enal cell carcinoma patients. Thus the impaired locomotion previously observed in TIL was at least partially due to the presence of tumor. T he locomotion of TIL was restored in four of five melanoma patients tr eated with liposome-encapsulated muramyl-tripeptide-phosphatidylethano lamine (L-MTP-PE). Furthermore, in six of seven examined L-MTP-PE-trea ted patients, an increase in intrinsic PBL locomotion during the first month of the therapy was observed. These results suggest that the env ironment of the tumor is not conducive to locomotion of advancing lymp hocytes and the therapeutic intervention may ameliorate the loss of ly mphocytic infiltration.