Modulation of immune response and tumor development in tumor-bearing mice treated by the thymic factor thymostimulin (original) (raw)
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Breast Cancer Research and Treatment, 1993
A detailed analysis of the immune system response has been performed during the development and progression of dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors. For this aim, a number of immune parameters (thymocyte and splenocyte proliferative response to T-dependent mitogens, antibody production, lymphocyte subset phenotyping, interleukin 2 receptor expression in resting and activated lymphocytes, thymus morphology and morphometry), were correlated with tumor appearance and growth at different (- 7, 0, + 15, + 30, + 60, + 90, and + 120 days) time intervals after intragastric administration of DMBA, in the absence or the presence of a concomitant treatment with the thymic pentapeptide thymopentin (TP5). A profound and time-dependent immunosuppression characterized the treatment with the carcinogen. Both cell-mediated and humoral immune responses showed a 50% inhibition 2 weeks after DMBA administration, with a peak after 30 days, followed by a plateau until 120 days of observation. The mechanism responsible for reduced ability of thymocytes and splenocytes to respond to both Con-A and PHA was explained by the significant inhibition of one of the key steps of T cell activation, namely the expression of IL-2 receptor in lymphocytes from DMBA-treated animals. The flow cytometric analysis of lymphocyte subpopulations revealed an important reduction in the overall populations of thymocytes and splenocytes. At the thymus gland level, a dramatic reduction of double positive CD4+CD8+ and a decrease of CD4+CD8- and CD4-CD8+ were observed, together with a marked atrophy of the thymic cortex, and impairment of the thymic microenvironment. One hundred and twenty days after DMBA administration, approximately 60 to 70% of the animals developed tumors with a mean tumor surface area of 2.88 ± 0.86 cm2, and a number of 2.44 ± 1.0. Treatment with TP5 (100 ng/animal, three times a week, starting a week before DMBA), produced specific effects on different immune compartments and tumoral growth, characterized by a significant reversal of immune depression with a stimulatory effect measured on lymphoproliferative assays, lymphocyte subset distribution, and IL-2 receptor expression. Moreover, thymic atrophy was almost completely prevented in TP5 treated animals. Of major interest, a significant delay in the appearance and growth of tumors was observed in TP5 treated rats. When DMBA-treated animals were followed for the entire observation period (0–120 days) and the immune responsiveness correlated according to tumor progression, stability, or regression, a positive correlation was calculated between the degree of immune system depression and the individual rate of tumor growth; in TP5-treated rats the majority of the tumors were static or regressing tumors. It is concluded that a profound and specific suppression of thymus-dependent immune functions follows the treatment with the carcinogen DMBA. Such immune deficits appear 2 weeks after the carcinogen administration, and may represent early indicators of tumor development and growth. A key role is suggested for the thymus gland and its peptide secretion, since the dramatic atrophy of this gland and the abnormal thymusdependent immune parameters studied are almost completely reversed by a synchronized treatment with thymopentin. Although from the present results it seems not possible to conclusively assign a specific causeeffect relationship, from the parallel delay in tumor appearance and growth in TP5-treated rats it seems tempting to speculate that the decline in thymus-dependent immune functions may play a major role in tumor development.
Cancer Immunology, Immunotherapy, 1998
mWe present the results obtained with an in vitro model system that resembles the in vivo tumour microenvironment, where malignant cells are in close contact with the infiltrating lymphocytes. Unmanipulated blood lymphocytes were cytotoxic against the autologous ex vivo tumour cells in 3/19 patients and this function was generated in 6-day mixed cultures in five additional cases. Production of transforming growth factor b (TGFb) by the freshly separated tumour cells was determined in parallel. Cytotoxicity was generated by a small number of tumour cells (2±5/100 lymphocytes), while a large number (10±20/ 100 lymphocytes) inhibited not only the generation but also the existing lytic activity. The presence of a neutralising TGFb-specific mAb (2G7) potentiated the activation of lymphocytes and suspended the suppression inflicted by the tumour cells. In those tumours, which expressed relatively high levels of MHC class I and ICAM-1 molecules, the quantity of secreted TGFb interfered with the ability of tumour cells to generate cytotoxic lymphocytes. In the tumours with low expression of class I, such a correlation was not detected, indicating the primordial role of MHC class I expression in the regulation of autologous tumour recognition. Our results demonstrate the involvement of TGFb in the impaired lymphocyte-mediated reactivity against immunogenic tumours and support a mechanism that contrasts the tolerance or anergy. Since presence of TGFb in the microenvironment of tumours counteracts the function of cytotoxic T lymphocytes, production of this cytokine can contribute to the failure of immunotherapy. Key wordsmHuman carcinoma ? Cytotoxic lymphocytes ? Transforming growth factor b ? Interferon g ? Tumor necrosis factor a N. Nagy ? F. Va Ânky ()
Effect of the thymic factor, thymostimulin (TP-1), on the survival rate of tumor-bearing mice
Cancer research, 1981
The effect of treatment with the thymic factor thymostimulin (TP-1) on the survival rate of tumor-bearing mice was studied, using C57BL/6 mice inoculated with 1 x 10(5) Lewis lung carcinoma (3LL) cells. TP-1 given from inoculation day (4 mg/kg, twice weekly) caused a delay in the appearance of primary tumor [14.4 +/- 1.1 (S.E.) days in control; 18.5 +/- 1.4 days in TP-1-treated animals; p less than 0.05], without changing ultimate survival rate. When primary tumor was resected, the incidence of fatal lung metastasis increased as a function of tumor size on resection day. TP-1 given after resection (same dose schedule) significantly increased survival rate as compared to resection only, provided that resected tumor diameter was less than 1.7 mm. The combination of TP-1 and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; single i.p. injection, 50 mg/kg) was effective in either resected or nonresected primary tumor. Without resection, TP-1 with CCNU cured (more than 6 months free o...
Nonspecific suppression of T lymphocyte responses in mice carrying progressively growing tumors
European Journal of Immunology, 1974
Unfractionated spleen cells from mice with four different types of progressively growing tumors were unable t o show enhanced DNA or protein synthesis upon stimulation with phytohemagglutinin (PHA) in vitro. After separation by velocity sedimentation, o r passage over an anti-immunoglobulin column, cells were obtained which could respond t o this mitdgen. An auxiliary population of cells obtained by velocity sedimentation, sedimenting with the characteristics of activated B lymphocytes and sensitive t o the cytotoxic effects of anti-immunoglobulin serum and complement, could depress the response of normal spleen cells challenged with PHA. A role for this cell type in the tumor progression seen in the host animals is discussed.
International Journal of Cancer, 1978
An immunopotentiating factor associated with spleen cells of C57BL/6J mice bearing the 3LL tumor is described. Supernatants of cultured spleen cells from tumor-bearing mice (TBM) augmented the generation of both 19S and 7S antibody-producing cells, when injected with sheep erythrocytes into syngeneic C57BL/6J mice. The enhancing supernatant acted both as a polyclonal activator, when injected in the absence of antigen, and as a potentiator of specific antigen-dependent humoral immune responses, when injected in the presence of antigen. It was found to augment induction of specific memory, but not memory expression. Concomitantly with their influence on humoral immune responses, TBM spleen cell supernatants enhanced tumor growth when injected, mixed with 3LL tumor cells, into syngeneic recipients. The secretion of a factor which augments antibody production was not confined to the 3LL tumor system. Spleen supernatants of C47BL mice carrying the B16 melanoma and those of C3H mice carrying the KHT sarcoma had a similar effect on antibody production. These findings suggest that an immunoregulatory factor(s) appears in spleen cells of TBM as a result of their interaction with the neoplastic tissue. This factor can potentiate production of antibodies, possibly also against tumor-associated antigens. The relevance of the immunopotentiating effects of such factor(s) to tumor growth is discussed.
Increase in immunogenicity of a pulmonary squamous-cell carcinoma, propagatedin vitro
International Journal of Cancer, 1977
The chemically induced, non-immunogenic lung squamous-cell carcinoma (MSC-10) propagated in vitro gradually loses tumorigenicity in immunocompetent hosts with increasing in vitro passage. This was found to be related to an increase in antigenicity, since immunosuppressed hosts (thymectomy plus 600 rads whole body X-irradiation) supported the growth of tumor cells, whereas immunocompetent recipients did not. The antigens involved in rejection are not heterologous serum proteins present in culture media since the cell line grown in isologous serum is also rejected. Immunization with the in vitro tumor line partially protected against the parental in vivo line, therefore the antigens involved must be present on both tumor lines. Inoculation of the cultured cell line into normal or immunosuppressed hosts produced tumors with the same histological characteristics as those of the in vivo tumor line. W e concluded that by in vitro culture the weakly antigenic carcinoma becomes more immunogenic and thereby capable of inducing transplantation resistance.
Stimulation of thymus- and bone marrow-derived lymphocytes by tumor cells in culture
Cancer research, 1977
In vitro lymphocyte stimulation by mitomycin-blocked tumor cells can be used to measure tumor-specific immune responses. In order to determine the responding cell type(s) in this reaction, lymph node and spleen cell populations were specifically depleted of thymus- or bone marrow-derived cells by the use of the appropriate antisera and complement or by immunoadsorption of the Fc receptor-bearing cells to antibody-coated sheep red blood cell monolayers. The compositions of both the original and the modified lymphocyte populations were determined by (a) viability counting following treatment with antisera and complement, (b) direct and indirect immunofluorescence, (c) antibody-coated erythrocyte rosette formation, and (d) response to thymus- and bone marrow-derived cell mitogens. In the lymph node cell populations, only the thymus-derived cells were stimulated by the tumor cells. However, both bone marrow- and thymus-derived cells from tumor-immune spleens underwent stimulation when e...
Early tumor effect on splenic Th lymphocytes in mice
Febs Letters, 1997
Tumors are characterized by their ability to avoid the host immune system. Ehrlich ascites tumor cells were used to investigate the early alterations of the host immune system after tumor inoculation. The results show that frequencies of splenic Th lymphocytes were drastically reduced during tumor growth, reaching a minimum only two days after tumor inoculation. The frequency of splenic CD4+ lymphocytes expressing IFN-γ was significantly increased, although the total number was unchanged, suggesting that there was no net induction of Th1-type response. Splenic macrophages were increased, in both frequency and cell number, after four days of tumor growth. The same pattern was observed when mice were inoculated with cell free ascitic fluid. TGF-β precursors were detected in tumor cells as well as in ascitic fluid. The data suggest that tumor actively interacts with host immune system by means of tumor cell secreted factors.