Immunosuppression by micromolecular fibrinogen degradation products in cancer

PATIENTS with advanced cancer and lymphoid malignancies often show impaired cellular and humoral immune responses, partly caused by serum factors inhibiting lymphocyte reactivity 1–3 , which, although not fully defined, are considered to be low molecular weight (poly)peptides. Another frequent finding in malignant diseases is the appearance of circulating fibrin(ogen) degradation products (FDPs) 4,5 . Besides the commonly investigated breakdown products X, Y, D and E, plasmin liberates several small peptides from human fibrinogen designated “micromolecular FDPs” 6 . These are dialysable, thermostable, have molecular weights between 15,000 and 500 (ref. 6) and have distinct physiological properties 7–10 . Since both the degree of impairment of lymphocyte function and the frequency of FDP formation are related to the extent of neoplastic spread 3,4 , we investigated the influence of micromolecular FDPs on cellular and humoral immune responses. A striking immunosuppressive activity was found, possibly responsible for impaired immunoresponsiveness in cancer patients. Terminal FDPs were obtained by prolonged digestion of human fibrinogen (Forschungsfibrinogen Kabi) with human plasmin (Forschungsplasmin Kabi) in aqueous solution, p H 7.4, and dialysed against distilled water at 4 °C for 24 h. The dialysate was concentrated by evaporation in a vacuum, reconstituted in physiological saline, sterilised by filtration and added to lymphocyte cultures using a microculture system 11 . As Fig. 1 shows, micro-molecular FDPs caused a dose-dependent suppression of PHA-induced lymphocyte transformation, which was 98% at 1.1 mg m1 −1 . These concentrations did not affect cell viability as measured by Trypan blue exclusion. Plasmin dialysates alone, prepared in identical conditions, inhibited neither of the systems tested: separation of fibrinogen on Sephadex G-200 showed no evidence of pre-existing contaminants (Fig.4).