Inadequate presentation of tumor antigens by host professional antigen-presenting cells (APCs), including dendritic cells (DCs), is one potential mechanism for the escape of tumors from the host immune system. Here, we show that human cancer cell lines release a soluble factor or factors that dramatically affect DC maturation from precursors without affecting the function of relatively mature DCs. One factor responsible for these effects was identified as vascular endothelial growth factor (VEGF). Thus, VEGF may play a broader role in the pathogenesis of cancer than was previously thought, and therapeutic blockade of VEGF action may improve prospects for immunotherapy as well as inhibit tumor neovasculature.

Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells.

https://www.cell.com/imto/pdf/0167-5699(92)90008-U.pdf

The origin and function of tumor-associated macrophages

Decreased immune function in cancer patients is well-characterized (I), and tumor cells have developed a variety of mechanisms, to avoid anti-tumor immune responses (2–8). One mechanism for inhibition of immune cell function by tumors in the production of soluble factors, such as IL-10, TNF, TGF-β, and Vascular Endothelial Growth Factor (VEGF). The effects of these factors appear, to be twofold: To inhibit effect or function and to impair the development of immune cells by acting on earlier stages of immunopoiesis. Immune suppression by tumors is accomplished by a variety of cellular and molecular mechanisms, and virtually all branches of the immune system can be affected. VEGF and its receptors have profound effects on the early development and differentiation of both vascular endothelial and hematopoetic progenitors (9). It induces proliferation of mature endothelial cells and is an important component in the formation of tumor neovasculature (10). VEGF is abundantly expressed by a large percentage of solid tumors and this over-expression is closely associated with a poor prognosis (11, 12). Some of the earliest hematopoetic progenitors express receptors for VEGF (13), and we have demonstrated that VEGF causes a defect in the functional maturation of dendritic cells (DC) from progenitors. This developmental defect is associated with impaired activation of NF-κB (14–17). This review describes research demonstrating that VEGF is not only important for tumor vascularization, but is also a key factor produced by solid tumors to inhibit recognition and destruction of tumor cells by the immune system.

VEGF as a mediator of tumor-associated immunodeficiency

Ovarian cancer is the most fatal gynecological cancer in the USA and the fifth most common cancer-related cause of death in women. Inflammation has been shown to play many roles in ovarian cancer tumor growth, with the proinflammatory cytokine interleukin-6 (IL-6) having been established as a key immunoregulatory cytokine. Ovarian cancer cells continuously secrete cytokines that promote tumorigenicity in both autocrine and paracrine fashions while also receiving signals from the tumor microenvironment (TME). The TME contains many cells including leukocytes and fibroblasts, which respond to proinflammatory cytokines and secrete their own cytokines, which can produce many effects including promotion of chemoresistance, resistance to apoptosis, invasion, angiogenesis by way of overexpression of vascular endothelial growth factor, and promotion of metastatic growth at distant sites. IL-6 and its proinflammatory family members, including oncostatin M, have been found to directly stimulate enhanced invasion of cancer cells through basement membrane degradation caused by the overexpression of matrix metalloproteinases, stimulate promotion of cell cycle, enhance resistance to chemotherapy, and cause epithelial-to-mesenchymal transition (EMT). IL-6 has been shown to activate signaling pathways that lead to tumor proliferation, the most studied of which being the Janus kinase (JAK) and STAT3 pathway. IL-6-induced JAK/STAT activation leads to constitutive activation of STAT3, which has been correlated with enhanced tumor cell growth and resistance to chemotherapy. IL-6 has also been shown to act as a trigger of the EMT, the hypothesized first step in the metastatic cascade. Understanding the important role of IL-6 and its family members' effects on the pathogenesis of ovarian cancer tumor growth and metastasis may lead to more novel treatments, detection methods, and improvement of overall clinical outcomes.

/pdf/il-6-and-ovarian-cancer-inflammatory-cytokines-in-promotion-4r1gviss5p.pdf

IL-6 and ovarian cancer: inflammatory cytokines in promotion of metastasis.

We examined the production and utilization of interleukin 6 (IL-6), a multifunctional cytokine with diverse biological effects, by both ovarian cancer cell lines and primary ovarian tumor cultures. We have found that epithelial ovarian cancer cell lines (CAOV-3, OVCAR-3, and SKOV-3) constitutively produce varying amounts of IL-6. This molecule is biologically active as determined by the proliferation of an IL-6-dependent hybridoma cell line, MH60.BSF-2, and is detectable by an IL-6 enzyme-linked immunosorbent assay. By cytoplasmic immunoperoxidase staining, greater than 98% of the cells produce at least some IL-6, with variation in the staining intensity between individual cells. The ovarian cancer cell-produced protein has a molecular weight of approximately 24,000, and exhibits some molecular weight heterogeneity, with Mr 27,000 and 28,000 minor forms of IL-6. The levels of IL-6 produced by ovarian cancer cells can be modulated by other inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma. Our results suggest that IL-6 is not an autocrine growth factor for these established ovarian tumor cell lines, because the addition of either exogenous IL-6 or antibodies to IL-6 did not affect the cellular proliferation of the cell lines. We also found significant levels (greater than 3 ng/ml) of IL-6 in ascitic fluids of ovarian cancer patients and in the supernants of primary cultures from freshly excised ovarian tumors. The production of IL-6 by epithelial ovarian cancer cells may prove to be a useful diagnostic tool and aid in investigation of the host immune response to ovarian cancer.

https://cancerres.aacrjournals.org/content/canres/50/21/6959.full.pdf

Constitutive Production of Interleukin 6 by Ovarian Cancer Cell Lines and by Primary Ovarian Tumor Cultures

Our study was designed to investigate the production of interleukin-1 (IL-1) and IL-6 in tumor-associated macrophages (TAM) isolated from ascites (18 cases) or solid (7 cases) human ovarian carcinoma. These are pleiotropic monokines which, in addition to affecting proliferation and differentiation of lymphocytes, act on various targets, including vascular cells and liver, and may therefore be involved in the pathogenesis of certain manifestations of malignancy. IL-1 was measured by the thymocyte co-stimulator assay, under conditions in which IL-6 was inactive, and, in 8 cases, by radioimmunoassay (RIA). IL-6 was measured as hybridoma growth factor (HGF) on the 7TD1 cell line. TAM did not release appreciable levels of IL-1 spontaneously and, upon LPS stimulation, were poor producers of this monokine compared to blood monocytes. In contrast, TAM supernatants contained a high level of HGF in the absence of deliberate stimulation, and exposure to LPS either did not affect or further augmented production of this monokine. HGF activity of TAM supernatants was completely blocked by anti-IL-6 antibodies. Ascites fluid from 8 ovarian-carcinoma patients contained high levels of HGF activity, blocked by anti-IL-6 antibodies. Thus, TAM exhibit a dissociation in their capacity to release the functionally related monokines IL-1 and IL-6. IL-6 produced by TAM may account for the elevation of liver-derived acute-phase proteins associated with malignancy.

IL-1 and IL-6 release by tumor-associated macrophages from human ovarian carcinoma.

Interleukin-1 (IL-1) is a cytokine with an important role in host defense against a number of inflammatory and immunologic challenges. Molecular studies have revealed the existence of two distinct but related species of IL-1, designated IL-1α and IL-1β, which act through a common receptor [6] and appear to have very similar if not identical, biological activities [15]. IL-1 induces the release of other cytokines such as IL-2 [23], inteferon [11], granulocyte-macrophage-colony-stimulating factor (GM-CSF) [25] and granulocyte-colony-stimulating factor (G-CSF) [24]. In vascular endothelium GM-CSF is involved in IL-1-induced colony-stimulating activity (CSA) [22]. Although different cell types have the capacity to produce IL-1, cells of the monocyte-macrophage lineage are a major source of IL-1 [19]. Upon appropriate stimulation, mononuclear phagocytes also release tumor necrosis factor (TNF), a monokine unrelated to IL-1 but with several biological activities [4,18]. IL-1 has been shown to have radioprotective activity in mice [17], an effect that may be related to its direct or indirect action on bone marrow precursors. The capacity of IL-1 to affect hemopoietic precursors together with its action on vessel wall hemostatic properties [14] prompted us to investigate the production of IL-1 in acute nonlymphoid leukemia (ANLL). We report that freshly isolated ANLL cells release considerable amounts of IL-1 upon endotoxin stimulation.

Interleukin-1 and tumor necrosis factor production in acute non-lymphoid leukemia

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IL-1 and IL-6 release by tumor-associated macrophages from human ovarian carcinoma.

Interleukin-1 and tumor necrosis factor production in acute non-lymphoid leukemia