Pre-treatment serum levels of interleukin-10, interleukin-12 and their ratio predict response to therapy and probability of event-free and overall survival in childhood soft tissue sarcomas, Hodgkin's lymphomas and acute lymphoblastic leukemias
Introduction
It has been stated that inflammation plays an essential role in cancer initiation and proliferation, and both tumor and inflammatory cells are able to influence tumor growth [1], [2]. The key point is the balance between the pro-inflammatory and anti-inflammatory cytokines [3], [4] secreted by the different CD4+ T helper lymphocyte subsets (termed Th1 and Th2 cells) [5], [6]. The polarization into Th1/Th2 cells depends on several environmental and genetic factors and particularly, on the local concentration of cytokines, such as IL-12 and IL-4, that induce differentiation of naive T lymphocytes to the Th1 and Th2 phenotype, respectively [7], [8]. The cytokines produced by the Th1 cells (interferon-gamma (IFN-γ), interleukin-2 (IL-2), IL-12, IL-15, lymphotoxin and tumor necrosis factor-alpha (TNF-α)) are generally pro-inflammatory and promote cell-mediated immunity to fight viruses and other intracellular pathogens, eliminate cancerous cells, and stimulate delayed-type hypersensitivity skin reactions [9]. In contrast, the Th2 cytokines (such as IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13) are essential for the induction of the humoral immune response and up-regulation of antibody production to fight extracellular organisms; type 2 dominance is credited with tolerance of xenografts and of the fetus during pregnancy [10].
The Th1 and Th2 cytokines act in an antagonistic fashion. IL-4 and IL-10 promote Th2 and antagonize Th1 development, whereas INF-γ and IL-12 promote Th1 and antagonize Th2 induction [8], [11], [12], [13]. The Th1/Th2 balance has been shown to play a critically important role in immunity regulation [4], [14], [15]. It has been suggested that a shift towards Th1 immune response and a down-regulation of the Th2 reactions may facilitate the induction of anti-tumor immunity [16], [17], [18]. This hypothesis has been proven in several experimental in vitro studies which have demonstrated an anti-tumor effect of Th1 cytokine, IL-12, able to activate the innate and antigen-specific adaptive immunity against tumor cells and to inhibit tumor angiogenesis through INF-γ [19], [20], [21]. Also in vivo experiments with the use of gene-modified tumor cells [22], fibroblasts [23], antigen-presenting cells [24], as well as by systemic administration of IL-12 [25], [26] have shown anti-tumor potential of IL-12. To the contrary, IL-10, the Th2 cytokine, has been reported to demonstrate mainly immunosuppressive and anti-inflammatory properties, suggesting its role in the inhibition of adequate anti-tumor immune responses [27], [28]. Since many tumor types including lymphomas, non-small cell lung cancer, melanoma, neuroblastoma, ovarian, renal cell, gastric, nasopharyngeal and colon carcinomas express and release IL-10 (either directly or indirectly) [29], [30], [31], [32], [33], [34], [35], its role in helping tumors evade immunosurveillance has been suggested [36], [37], [38]. Indeed, elevated levels of IL-10 have been reported in sera from patients with different histotypes of solid [31], [39], [40], [41] and hematopoietic tumors [36], [42], [43], [44], [45], suggesting that a predominant Th2 pattern of cytokine secretion is commonly operative at the tumor site.
In the vast majority of cancers the elevated levels of serum IL-10 have correlated with the extent of the disease [36], [46] and other established negative prognostic factors [39], [40], [43], [47], [48] as well as with shorter overall survival [28], [31], [49]. Thus it has given rise to the hypothesis that IL-10 may provide better conditions for tumor growth [30]. Since IL-10 is a potent inhibitor of the IL-12 synthesis by the antigen-presenting cells, it may be expected that elevated IL-10 levels are accompanied by the decreased levels of IL-12, which represents a switch from Th1 to Th2 type immune response in the active phase of malignant disease. Indeed, the antagonistic role of IL-10 and IL-12 has been demonstrated in a variety of tumor types [50], [51], [52]. Also some clinical observations have confirmed that diminished Th1 and an enhanced Th2 immune responses correlate with more advanced, metastatic or highly aggressive malignancy [53], [54] when compared to that of patients with less advanced disease with better prognosis where the shift towards Th1-dominant response usually occurs [55], [56].
There have been several reports on the levels of IL-10 or IL-12 in different non-neoplastic pediatric disorders [57], [58], [59], [60], [61]. However; to our best knowledge there have been no published studies concerning the role of two pivotal Th2 and Th1cytokines (IL-10 and IL-12, respectively) and their balance in childhood malignancies. Because soft tissue sarcomas (STS), Hodgkin's lymphomas (HL) and acute lymphoblastic leukemias (ALL) developing in children vary in most instances from their adult counterparts, we decided to investigate the clinical roles of serum IL-10, IL-12 and their ratio in children with newly diagnosed STS, HL and ALL. Of our particular interest were the diagnostic and prognostic significance of the pre-treatment IL-10, IL-12 and IL-10/IL-12 ratios and their possible correlation with other well-known clinico-pathological prognostic factors, other indirect biochemical markers used commonly in oncologic practice (erythrocyte sedimentation rate—ESR, C-reactive protein—CRP and lactate dehydrogenase—LDH), the response to chemotherapy (CHT), relapse occurrence and overall (OS) as well as event-free survival (EFS). The possible clinical diagnostic and prognostic roles of IL-10, IL-12 and their ratio may be of special value in STS patients as they lack any reliable biochemical tumor marker.
Section snippets
Patients
The study comprised 91 children with three different histological types of cancer, including: STS, HL and ALL diagnosed and treated in the Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical University of Gdansk, Poland between 1995 and 2004. The group comprised 46 females and 45 males aged from 1.3 to 18 years, mean age 10.4, median age 11.1 years. The median age of patients of the STS subgroup was 9.4 years, of the HL subgroup—15.4 years and of the ALL subgroup—6.2 years.
Results
All 30 healthy children included in the control group had detectable serum levels of IL-10 and IL-12. The results of serum IL-10, IL-12 and IL-10/IL-12 ratios as well as of ESR, CRP and LDH obtained from healthy controls and from cancer patients (in the whole group—91 children and in three different histotypes including STS-30 patients, HL-30 and ALL-31) are shown in Table 1.
Discussion
Most childhood malignancies lack reliable and specific biochemical tumor markers correlating with disease extent and aggressiveness. That is why several non-specific indirect indicators, including ESR, CRP and LDH, are used in common practice as additional diagnostic and prognostic tools. The study presented here is the first one aimed to assess whether pre-treatment serum levels of IL-10 and IL-12 might play a clinical role in selected pediatric malignancies, similar to that observed in the
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