Changes in spleen morphology and lymphoid cell activity during tumor progression

doi:10.1016/0014-2964(80)90050-X

European Journal of Cancer (1965)

Volume 16, Issue 11, November 1980, Pages 1417-1426

European Journal of ...

https://doi.org/10.1016/0014-2964(80)90050-X Get rights and content

Abstract

Morphologic alterations in the spleen and dynamic changes in the biologic activity of its cellular components occur concomitant with the neoplastic progression of a murine methylcholanthrene induced fibrosarcoma. Spleen size, weight and cell number increased with tumor growth. Using the local adoptive transfer assay (LATA), spleens from tumor bearing mice in the early and late stages of neoplastic growth were shown to possess non-specific, tumor-facilitating cells which were radioresistant, phagocytic and adherent, presumably macrophages. On the other hand, spleens from mice in the intermediate and late stages of tumorigenesis displayed specific, tumor-neutralizing cells, which were radiosensitive and Thy 1.2 positive, presumably T-cells. Thus, a balance of tumor-facilitating and neutralizing cells may determine neoplastic progression in susceptible, syngeneic hosts.

References (31)

L.G. Baird et al.
Macrophage regulation of mitogen-induced blastogenesis. I. Demonstration of inhibitory cells in the spleens and peritoneal exudate of mice
Cell. Immunol.
(1977)
J.R. Oehler et al.
Inhibition of rat mixed lymphocyte cultures by suppressor macrophages
Cell. Immunol.
(1977)
H. Yamagishi et al.
Tumor-protective and facilitating antigens from 3M KCl solubilized tumor extracts
J. surg. Res.
(1979)
H. Kirchner et al.
Suppression of in vitro lymphocyte stimulation in mice bearing primary Moloney sarcoma virus-induced tumor
Cell. Immunol.
(1974)
I. Berczi et al.
Effector and suppressor lymphoid cells in tumor-bearing guinea-pigs
Int. J. Cancer
(1979)
R.M. Gorczynski
Immunity to murine virus-induced tumors. II. Suppression of T cell-mediated immunity by cells from progressor animals
J. Immunol.
(1974)
R. Evans et al.
Co-operation of immune lymphoid cells with macrophages in tumor immunity
Nature (Lond.)
(1970)
J.M. Zarling et al.
Transplantation immunity to Simian virus 40-transformed cells in tumor-bearing mice. II. Evidence for macrophage participation at the effector level of tumor cell rejection
J. nat. Cancer Inst.
(1973)
R.B. Herberman et al.
Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. I. Distribution of reactivity and specificity
Int. J. Cancer
(1975)
S. Fujimoto et al.
Regulation of the immune response to tumor antigens. I. Immunosuppressor cells in tumor-bearing hosts
J. Immunol.
(1976)

S. Fujimoto et al.

Regulation of the immune response to tumor antigens. II. The nature of immunosuppressor cells in tumor-bearing hosts

J. Immunol.

(1976)

K. Kakimoto et al.

Enhanced tumor growth caused by anti-Th-B antiserum due to a possible activation of suppressor T-cells

Cancer Res.

(1977)

V. Rotter et al.

Inhibition of tumor growth in syngeneic chimeric mice mediated by a depletion of suppressor T cells

Transplantation

(1975)

M. Small

Characteristics of the immature cells involved in T-cell-mediated enhancement of syngeneic tumor growth

J. Immunol.

(1978)

A.J. Treves et al.

Enhancing T lymphocytes from tumor-bearing mice suppress host resistance to a syngeneic tumor

Europ. J. Immunol.

(1974)

Cited by (9)

Tumor cell derived osteopontin and prostaglandin E2 synergistically promote the expansion of myeloid derived suppressor cells during the tumor immune escape phase
2024, International Immunopharmacology
The immune escape stage in cancer immunoediting is a pivotal feature, transitioning immune-controlled tumor dormancy to progression, and augmenting invasion and metastasis. Tumors employ diverse mechanisms for immune escape, with generating immunosuppressive cells from skewed hematopoiesis being a crucial mechanism. This led us to suggest that tumor cells with immune escape properties produce factors that induce dysregulations in hematopoiesis. In support of this suggestion, this study found that mice bearing advanced-stage tumors exhibited dysregulated hematopoiesis characterized by the development of splenomegaly, anemia, extramedullary hematopoiesis, production of immunosuppressive mediators, and expanded medullary myelopoiesis. Further ex vivo studies exhibited that conditioned medium derived from EL4lu2 cells could mediate the expansion of myeloid derived suppressor cells (MDSCs) in bone marrow cell cultures. The protein array profiling results revealed the presence of elevated levels of osteopontin (OPN), prostaglandin E2 (PGE2) and interleukin 17 (IL-17) in the culture medium derived from EL4luc2 cells. Accordingly, substantial levels of these factors were also detected in the sera of mice bearing EL4luc2 tumors. Among these factors, only PGE2 alone could increase the number of MDSCs in the BM cell cultures. This effect of PGE2 was significantly potentiated by the presence of OPN but not IL-17. Finally, in vitro treatment of EL4luc2 cells with pioglitazone, a modulator of OPN and cyclooxygenase 2 (COX-2) resulted in a significant reduction in cell proliferation in EL4luc2 cells. Our findings highlight the significant role played by tumor cell-derived OPN and PGE2 in fostering the expansion of medullary MDSCs and in promoting tumor cell proliferation. Furthermore, these intertwined cancer processes could be key targets for pioglitazone intervention.
Evidence for involvement of TNF-α in the induction phase and IFN-β in the effector phase of antiproliferative activity of splenic macrophages
1992, Cellular Immunology
Splenic macrophages play a key role in regulating cell proliferation during a variety of chronic perturbations of the hematopoietic system. This regulatory activity is in sharp contrast to the activities of inflammatory monocytes/macrophages in that it is not dominated by the secretion of prostaglandins or toxic metabolites such as peroxides. A productive model for studying these nontoxic regulatory activities of splenic macrophages has been provided by macrophages generated in vitro (Mø-c) during autologous spleen cell culture. The Mø-c effectively inhibit (>90%) lymphocyte proliferation by inhibiting G1→S phase progression without inhibiting the production of interleukins by the lymphocytes. Conditioned medium from Mø-c activated with LPS + rIFN-γ effected a similar G1 arrest of activated lymphocytes. The involvement of IFN-β in effecting the antiproliferative activity is suggested by (1) the ability of monospecific anti-IFN-β mAB, but not anti-TGF-β, anti-IL-1, anti-TNF-α, or anti-IFN-γ, to neutralize the antiproliferative activity in the Mø-c supernatants and (2) the ability of purified IFN-β to effect a similar inhibition of cell proliferation (i.e., G1 arrest without inhibition of interleukin production). rTNF-α and rIFN-γ could not effect such an inhibition of cell proliferation and did not synergize with IFN-β in producing such an antiproliferative effect. The Mø-c could be activated to effector function by a combination of LPS + rIFN-γ or rTNF-α + rIFN-γ, but not by any one of those reagents alone. LPS alone was sufficient to stimulate TNF-α production by the Mø-c. Activation of the Mø)-c by LPS + rIFN-γ could be completely blocked by anti-TNF-a antibodies. These data suggest that the Mø-c can be induced to produce inhibitory levels of cytostatic cytokines by a TNF-α autocrine loop that is IFN-γ dependent. The in vivo relevance of this effector mechanism is suggested by, and discussed in the context of, the recent reports of “spontaneous” production of IFN-β during immunological disorders.
Cell-mediated inhibition of proliferation and activation of alloreactive cytotoxic lymphocytes: Maintenance of response potential of precursors and dissociation between proliferation and effector function of activated cytotoxic lymphocytes
1986, Cellular Immunology
Adherent layers of macrophages (Mφ-c) generated in vitro from splenic precursors inhibit lymphoproliferative responses to mitogen and to alloantigen without inhibiting the production of interleukin-2 (IL-2). Analysis of spleen cells stimulated for 48 hr in the presence of Mφ-c indicated that both blastogenesis (increased cell mass) and expression of IL-2 receptors (7D4 determinants) were reduced. Analysis of BrdU incorporation (frequency of S-phase cells) and total cellular DNA revealed that the Mφ-c inhibited the progression from G₁ to S phase of cell cycle. The Mφ-c not only inhibited the proliferative response to alloantigen but also prevented the generation of alloreactive cytotoxic T cells. The Mφ-c were shown not to inhibit CTL responses by eliminating the stimulators or by inactivating precursors or inducing suppressors. The Mφ-c were affecting the induction of CTL activity since the Mφ-c did not affect the expression of cytolytic activity by activated CTL. The Mφ-c did inhibit the proliferation of the activated CTL, suggesting that although cytolytic activity can be expressed in G₁ phase of cell cycle, the activation of cytolytic activity in CTL-P may require a G₁ to S phase transition. The cells recovered from 5-day MLC incubated in the presence of Mφ-c were fully capable of generating a subsequent CTL response. This is in contrast to cells recovered from unstimulated cultures (no Mφ-c) which have lost the ability to generate CTL responses. The Mφ-c therefore prevent the generation of CTL responses in a totally reversible fashion, so as to allow activation and proliferation of CTL-P which have been removed from the influence of the Mφ-c. These observations are discussed in the context of the currently hypothesized role of tissue macrophages in microenvironmental regulation.
Changes in splenic histology and cytology in mice bearing plasmacytomas
1984, Cellular Immunology
Studies of immunosuppression in plasmacytoma-bearing mice (PC-mice) yield important information for understanding a variety of immune phenomena. Most investigations of this model system have utilized splenic cells; thus, valid interpretation of much of this data rests on knowledge of the nature of the cells present in the spleens of PC-mice (PC-spleen). Nevertheless, no comprehensive description of PC-spleens has ever been made and is therefore the subject of this report. Major differences exist between normal and PC-spleens. PC-spleens are enlarged and contain an increased number of cells, the greater proportion of which are large in size. On the basis of morphology and expression of cell surface markers the absolute number of B cells and T cells per spleen was found to be normal or somewhat increased in PC-mice. However, the percentage of these cells was decreased due to an increase in other cell types causing changes predominantly in the red pulp of the spleen. The major populations expanded are polymorphonuclear leukocytes and macrophages. The numbers of megakaryocytes, immature precursor cells, and metastatic tumor cells are also increased to a smaller degree. The implications and relevance of these data to studies of PC-induced immunosuppression are discussed.
Epigenetic modification in 4T1 mouse breast cancer model by artificial light at night and melatonin–the role of DNA-methyltransferase
2019, Chronobiology International
Effective immunotherapy against cancer: A question of overcoming immune suppression and immune escape?
2004, Cancer Immunology, Immunotherapy

View all citing articles on Scopus

^☆: Supported by Grant IM-62E from The American Cancer Society.

View full text

Changes in spleen morphology and lymphoid cell activity during tumor progression☆

Abstract

Cell. Immunol.

Cell. Immunol.

J. surg. Res.

Cell. Immunol.

Effector and suppressor lymphoid cells in tumor-bearing guinea-pigs

Int. J. Cancer

Immunity to murine virus-induced tumors. II. Suppression of T cell-mediated immunity by cells from progressor animals

J. Immunol.

Co-operation of immune lymphoid cells with macrophages in tumor immunity

Nature (Lond.)

Transplantation immunity to Simian virus 40-transformed cells in tumor-bearing mice. II. Evidence for macrophage participation at the effector level of tumor cell rejection

J. nat. Cancer Inst.

Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. I. Distribution of reactivity and specificity

Int. J. Cancer

Regulation of the immune response to tumor antigens. I. Immunosuppressor cells in tumor-bearing hosts

J. Immunol.

Regulation of the immune response to tumor antigens. II. The nature of immunosuppressor cells in tumor-bearing hosts

J. Immunol.

Enhanced tumor growth caused by anti-Th-B antiserum due to a possible activation of suppressor T-cells

Cancer Res.

Inhibition of tumor growth in syngeneic chimeric mice mediated by a depletion of suppressor T cells

Transplantation

Characteristics of the immature cells involved in T-cell-mediated enhancement of syngeneic tumor growth

J. Immunol.

Enhancing T lymphocytes from tumor-bearing mice suppress host resistance to a syngeneic tumor

Europ. J. Immunol.