Studies on the Cellular Immunity in Tumor Bearers. Report 2. Serum-inhibitory Factors for PHA response of lymphocytes in patients with gastric carcinoma

Increasing evidence supports the view that human neoplasms, as in the case of animal tumors, possess tumor-specific or associated antigens. In most cases, however, anti-tumor immunity is apparently ineffectual and appears to be incapable of inhibiting cancer growth. In recent years, a number of studies have disclosed that there is a generalized depression of cellular immunity in individuals afflicted by neoplastic disorders. In particular the mechanism of the suppressed reactivity of thymus derived lymphocytes to tumor cells has not been clarified, however, it is postulated that abnormalities of lymphocytes themselves and/or effects of inhibitory serum factors are responsible. In the present report the effects of sera from patients with gastric carcinoma on lymphocyte responsiveness to phytohemagglutinin (PHA) were made and further isolation of serum-inhibitory factors were carried out. Responsiveness of cultured lymphocytes from patients with gastric carcinoma to PHA were markedly depressed in the presence of autologous sera as compared to normal controls. The reduced reactivities of lymphocytes in advanced gastric carcinoma showed restoration of their activities by an addition of normal sera. In contrast, the reactivities of normal lymphocytes to PHA were significantly inhibited by the addition of sera from patients with gastric carcinoma. In general, the suppressive effects of cancerous sera were observed mostly in carcinoma of advanced stages but not in the early stages. In order to elucidate the mechanism of humoral factors responsible for suppressed lymphocyte function, isolation of serum factors was carried out by means of column chromatography with microcrystalline DEAE-cellulose. The elution profiles of normal and cancerous sera were quite similar and the resulting eluents were separated into eleven fractions. Following dialysis and concentration with Diaflo membrane (UM-10), each fraction was subjected to bioassay to determine the localizations of inhibitory activities. Among fractions from normal sera Frs. 4, 7, 8 and 9 which correspond to alpha- and beta-globulins respectively revealed substantial suppression on PHA responsiveness of normal lymphocytes. In the fractions prepared from cancerous sera, alpha and beta-globulin fractions also showed remarkable suppressions on PHA responsiveness of lymphocytes. In addition to these results albumin rich fraction of cancerous sera revealed a definite suppressive activity on PHA responsiveness of normal lymphocytes. Furthermore no effects were observed on the attachment of 125I-PHA to the cell surface of normal lymphocytes in sera from cancer patients together with fractionated proteins obtained from both sera. Similarly, the albumin rich fraction obtained from cancerous sera inhibited the direct plaque-forming cell response (PFC) in mice when treated prior to immunization with SRBC, whereas the albumin rich fraction obtained from normal serum showed no inhibitory effect on PFC. The above findings strongly indicate that the function of lymphocytes in vivo may be regulated by a variety of humoral factors including IRA and in cancer patient the impairement of T-cell activity is affected by the presence of some specific factors not present in normal sera