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The effect of tumor growth on the suppressor cell activity of melanoma patients was examined by measurement of immunoglobulin produced in vitro in pokeweed mitogen (PWM)-stimulated cultures of B and T lymphocytes. B and T cells were separated by sheep red blood cell rosetting and suppressor cell activity was assessed by comparison of immunoglobulins produced in cultures with irradiated T cells (2,000 rads) to that with unirradiated T cells. In the majority of patients with localized melanoma, radiosensitive suppressor T cells were detected and appeared to be an augmentation of a normal physiological state. In patients with Stage I and II melanoma, removal of the tumor resulted in a significant decrease in suppressor activity against IgA and IgM but not against IgG production. Similar sequential changes in suppressor cell activity against IgA and IgM but not against IgG production. Similar sequential changes in suppressor cell activity were not generally detected in patients who had surgery for skin graft after previous removal of the primary melanoma or in patients undergoing surgery for non-malignant conditions. Sequential studies on the levels of serum immunoglobulins showed an apparent trend for immunoglobulins to increase after surgery. Of particular importance, the decrease in in vitro suppressor cell activity against IgM and IgG production after tumor removal in individual patients was significantly associated with an increase in immunoglobulin levels in the serum of these patients. It is suggested that these findings may account in part for the absence of detectable antibody responses to melanoma antigens in many patients and for the generalized immunodeficiency in patients with disseminated melanoma.

Previous reports of an association between cigarette smoking and the depression of immune function were investigated by studies of 35 subjects before, and three months after, they had ceased to smoke cigarettes. The studies included tests of natural killer cell (NK) activity against several target cells and the measurement of immunoglobulin levels in sera and saliva. Similar tests were conducted on 29 control subjects who continued to smoke. The results indicated a significant decrease in lymphocyte counts and a significant increase in NK activity against cultured melanoma cells in subjects who ceased smoking. Serum IgG and IgM levels rose significantly in those who ceased smoking cigarettes, but there was no change in IgA levels. Similar increases in immunoglobulin levels (IgA and IgG) in mucosal secretions (saliva) were noted after cessation of smoking. The NK activity and immunoglobulin levels of smokers who continued to smoke did not show significant changes. These results were consistent with the reversal of changes in immune function associated with smoking. We suggest that these findings may provide further insight into the association of smoking with an increased incidence of certain malignant diseases and respiratory infections.

Summary: Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis in melanoma by interaction with death receptors TRAIL-R1 (DR4) or TRAIL-R2 (DR5) on melanoma cells or resists apoptosis by interaction with decoy receptors TRAIL-R3 (DcR1) or TRAIL-R4 (DcR2). Studies on cell lines suggest that there is a wide variation in TRAIL death receptor expression; however, their expression on excised human melanoma is not well documented. In view of this, we studied death receptor expression on melanomas using monoclonal antibodies specific for these receptors. Immunohistochemical staining for DR4, DR5, and DcR1/DcR2 was performed on formalin-fixed paraffin-embedded sections of 100 cases of primary melanoma, metastatic melanoma, and benign nevi. Percentage expressions of DR4 versus DR5 in benign nevi, primary melanoma, and melanoma metastases were 40% versus 90%, 69% versus 98%, and 55% versus 66%, respectively. There were significant differences in the mean percentage of DR5-positive cells between different groups of melanocytic lesions. Percent expression was higher in thin (≤1.0 mm) compared with thick primary melanoma (88.9% versus 66.9%), and expression was less in subcutaneous metastases (49%) and lymph node metastases (30.6%) (P < .005). Expression was also higher in compound nevi (57%) than dysplastic nevi (49%). DcR1/DcR2 was found in 75% of benign nevi, 62% of primary melanomas, and 74% melanoma metastases. The results showed a wide variation in the expression of death receptors for TRAIL between and within primary and metastatic melanoma and a decreased expression on the thick primary melanoma and metastatic melanoma. This suggests that melanoma may not respond to treatment with TRAIL unless given with agents that increase the expression of TRAIL death receptors. [Copyright &y& Elsevier]

A number of previous studies have described antibodies in normal sera reactive to human leukaemia cells. In the course of studies on humoral immunity to acute myeloid leukaemia (AML) cells it was noticed that sera from normal subjects were cytotoxic in complement lysis and leucocyte dependent antibody (LDA) assays to blood leucocytes from patients with AML in remission. Investigation of these reactions in eleven patients with acute leukaemia in complete or partial remission revealed that reactivity occurred most frequently between sera from normal blood group O or B subjects and leucocytes from patients of blood group A (five patients). Leucocytes from blood group O patients were largely unreactive. Blood leucocytes from five of six patients in relapse did not react with normal sera. Subsequent studies revealed that the antigens were detected only on T lymphocytes. Reactivity could be removed by absorption on red cells of blood group A but not sheep or Ox red blood cells suggesting the antigens concerned were closely related to blood group A antigens. Some reactivity with antisera to the blood group H antigens was also evident in these studies. Gel filtration studies indicated that lymphocyte dependent antibody mediated cytotoxicity was mediated by IgG antibodies while complement dependent lysis was mainly mediated by IgM antibodies. The biological significance of these findings has yet to be determined hut these results suggest that reactivity with blood group antigens needs to he considered in in vitro cytotoxicity. [ABSTRACT FROM AUTHOR]

The effector cells responsible for cytotoxic activity induced by phytohaemagglutinin, (PHA) pokeweed mitogen (PWM) and target cells complexed with lgG antibody has been investigated using cell separation techniques based on rosette Formation and separation through Hypaque-Ficoll mixtures. It was shown that PHA-induced cytotoxicity is predominantly a function of T cells and that Fc receptor-bearing cells are not involved to any major extent. Antibody-dependent killing is conversely a function of Fc receptor-bearing cells among which two subtypes can be distinguished. One of these has receptors for activated complement while the other bears receptors only and has no detectable receptors for complement. PWM appears to induce cytotoxicity in both T- and non-T-cell populations but the major cell type involved appears to be Fe receptor-bearing cells similar to those mediating antibody-dependent killing. It is concluded that PHA and antibody- dependent killing are the two most useful assays for discriminating between the cytotoxic activity of T and non-T cells in clinical studies. [ABSTRACT FROM AUTHOR]

Antibodies which are to induce the killing of allogeneic myeloblasts by normal lymphoid cells have been found in a high proportion of patients with acute myeloid leukaemia. The cytotoxic mechanism induced by this antibody activity is shown to be highly effective in terms of the number of myeloblasts which can be killed by a given number of lymphoid cells and the antibody concentration needed to induce killing. Reasons for the in vivo failure of this cytotoxic mechanism, assuming that antibodies occur against autologous myeloblasts, are suggested by studies in which the cytotoxic lymphoid population has been monitored serially. Some patients are shown to have almost undetectable levels of cytotoxic effector cell activity. A further reason for the failure of this mechanism related to 'blocking activity' in the serum is being investigated. Preliminary results suggest that assay of this antibody activity against myeloblasts may also be of value in following the response to immunotherapy and in providing early warning of relapse. It is suggested that the demonstration of antibody-dependent lymphocyte activity against acute myeloid leukaemic cells provides an additional insight into this disease which may have important implications in management and therapy of acute myeloid leukaemia. [ABSTRACT FROM AUTHOR]

Rat lymphoma cells sensitized with antibody and incubated with normal macrophages were shown to become resistant to damage from cytotoxic antibody and complement or cytotoxic lymphocytes. Both lymphoma specific antibody and normal macrophages were required to produce protection. The cytotoxic effect of lymphocytes or antibody with complement and the protective effect of antibody with macrophages was assessed by 51Cr release and by loss of capacity of iymphoma cells to transfer the disease to syngeneic rats. No cytotoxic effect could be attributed to macrophages from sensitized allogeneic rats. Inhibition of phagocytosis by Cytochalasin B did not destroy the capacity of macrophages to protect lymphoma cells. Sodium fluoride, however, did block the protective effect. It is envisaged that this protective phenomenon may be of importance in understanding some aspects of growth of tumours in vivo despite the presence of immune cytotoxic mechanisms. [ABSTRACT FROM AUTHOR]

The evaluation of interferons in the treatment of malignant melanoma has been mainly in the treatment of advanced disease using interferons as the sole agent or in combination with other agents. Studies of the value of interferons as adjuvant therapy in high-risk primary melanoma patients are necessary, but no results have been published to date. Human interferon alpha produces low response rates as a sole agent, but in combination with cimetidine, a 30% response rate has been achieved. Recombinant alpha interferons give responses of 15%-20% in advanced melanomas, and combination with cimetidine does not enhance the response rate. Recombinant alpha interferons have been used in combination with other interferons, cimetidine, monoclonal antibodies, and cytotoxics, with either no or small improvement in response rates. DTIC with recombinant interferon alpha-2a has been shown to produce objective response rates of 26%, with low toxicity and maintenance of quality of life. A randomized trial with DTIC as the sole agent, compared with combination treatment, is being conducted to determine the significance of this finding. [ABSTRACT FROM AUTHOR]