The role of soluble fibrin in lymphocyte and LAK cell adherence to and diapedesis across endothelial cells: implications for immunotherapy and cancer

Adoptive immunotherapies have sporadic, but spectacular success in malignant melanoma. Soluble fibrin (sFn), a coagulation protein elevated in melanoma, inhibit the immune response against cancers, via blockade of integrin (LFA‐1) binding to tumor cell CD54: receptors important in endothelial cell (EC) adherence and diapedesis (homing). It was hypothesized that blockade of sFn mediated inhibition using specific peptides would restore these immune responses. Fluorescently labeled lymphocytes and Interleukin‐2 activated lymphocytes (LAK cells) were incubated with sFn in the presence or absence of specific blocking peptides, and their adherence to EC monolayers was measured by perfusion at physiological shear rates in a microscope perfusion chamber. Diapedesis was measured by detection of fluorescence following immune cell incubation with EC monolayers. sFn inhibited lymphocyte (54.0 + 11.3 %) and LAK cell (43.9 + 4.4 %) adherence to sFn pre‐treated EC, which was restored by peptide blockade of sFn/CD54 binding, but not by CD11b blocking peptides. Diapedesis was also inhibited by sFn (Lymphocyte 29.6 + 7.7 %; LAK 12.2 + 4.9 %) and restoration was observed using blocking peptides. These results support our hypotheses, suggesting that sFn may be an etiological agent in tumor growth and metastasis, and that blockade using fibrin specific peptides may enhance the effectiveness of adoptive immunotherapies.