To identify eligible studies, I did systematic searches of PubMed repeatedly over a period of 5 years up to 2012 for all individual cytokines in patients with cancer with the keywords “IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, IL-18, TNF-alpha, TGF-beta, interferon-γ HLA-DR, MIF or CXCR4” in combination with “serum level”, “patients”, “cancer”, “prognosis” and “metastases”. C-X-C motif chemokine receptor 4 (CXCR4) and HLA-DR are not cytokines, but were reviewed
ReviewCytokine patterns in patients with cancer: a systematic review
Introduction
The immune system can recognise transformed cells, and both innate and adaptive immune reactions to cancer have long been described. The tumour microenvironment contains macrophages, neutrophils, mast cells, myeloid-derived suppressor cells, dendritic cells (DCs), natural killer (NK) cells, and T and B lymphocytes.1 Tumour-associated antigens and T lymphocytes that are able to recognise tumour-specific antigens have been described.2, 3, 4, 5 Tumour-associated macrophages and tumour-infiltrating leucocytes accumulate within neoplastic tissue.6 Activated immune effector cells, such as NK cells, cytotoxic T cells, and macrophages, are present both at the tumour site and in the circulation of patients with cancer, but immune responses against cancer seem to be dysfunctional and tumours progress despite existing immunological activity.5, 7
The possibility of local tumour immune escape or even tumour-induced immune suppression has been studied and discussed in detail.7, 8, 9 The term immunoediting has been used to describe the immunological selection of resistant tumour variants by elimination of immunosensitive malignant cells.10, 11 The resulting avoidance of immune destruction has been defined as a hallmark of cancer.12 An inflammatory microenvironment seems to be a consistent component of malignant tumours, suggesting the presence of a cancer-related immune reaction.1, 6 As summarised by Mantovani and colleagues,6 there is increasing evidence that inflammation contributes to the development of cancer and also that cancer seems to directly promote the generation of an inflammatory microenvironment. Trinchieri13 stated in a recent review of the links between inflammation and cancer that “the class of inflammation and immunity that is responsible for tumour initiation and early progression is likely also to be the same class that makes the immune system unable to destroy the tumours successfully”. Whether inflammatory conditions increase the local cancer risk or if genetic alterations such as oncogenes cause inflammation and neoplasia is so far unclear,6 but that cancer cells actively interfere with the patient's immune system has been established. Several recent reviews summarised the cellular interaction between cancer and the immune system in the tumour microenvironment.7, 8, 9 However, with respect to the heterogeneity of cancer, a theory of a common or uniform immune reaction pattern seems so far to be obsolete.
Cytokines are intricately involved in all immune reactions. Since cytokines interfere directly or indirectly with each other's expression, the isolated effect of one cytokine can seem less relevant unless assessed in the context of its position in the hierarchy of a defined cascade. Cytokine interactions comprise sophisticated interdependent positive and negative feedback mechanisms, thus providing homoeostasis and immune control. Any attempt to outline these feedbacks in a model is necessarily simplistic because a more accurate representation of a large feedback system, ideally through a mathematical model, would create a non-linear and practically unpredictable relation. Isolated cytokine reactions have been described in individual tumour types, but so far no systematic model of the cytokine-related immune reaction in patients with cancer has been developed.
In summary, there is increasing evidence from experimental studies that malignant tumours utilise local mechanisms within their microenvironment to prevent activation of immunological effector functions, thereby protecting the tumour from a potential immune attack.8, 9
I undertook the present Review of cytokine interactions in patients with cancer with an emphasis on the immunological mechanisms that are associated with clinical disease progression. The approach is intentionally descriptive. Because of this narrow focus, several aspects of cytokine activation and signalling mechanisms were not considered. The format of the present Review is an initial step to detect common patterns in the immune response in patients with cancer, which so far might not be fully represented in experimental systems. The aim of the present Review was to point out reproducible and consistent features among reported clinical data in many and unrelated cancer types. By this translational approach, I attempt to use the context of recent experimental data to interpret the clinical findings. The working hypothesis here is that the emerging cytokine pattern potentially is a manifestation of the underlying systemic paraneoplastic immune response that seems to be a consistent pattern in patients with cancer. Further specification of this system could offer novel therapeutic approaches.7
Section snippets
Transforming growth factor β
Transforming growth factor β (TGFβ) has been suggested to be the principal immune-suppressive factor secreted by tumour cells.14 In mice, complete knockout of TGFβ1 results in lethal autoimmunity from a multiorgan inflammatory syndrome.15 TGFβ suppresses interleukin 12 substantially and inhibits interleukin 2 and interleukin-2-induced proliferation in T cells.16, 17 In CD8+ cytotoxic T lymphocytes and NK cells, TGFβ is a strong antagonist of interferon-γ production. TGFβ has a negative effect
C-X-C motif chemokine receptor 4
Chemokines are molecules that direct cells to specific organs. The chemokine stromal cell-derived factor-1 (SDF-1, also known as CXCL12) binds to C-X-C motif chemokine receptor 4 (CXCR4).22 CXCR4 is expressed in malignant tumour cells whereas its ligand SDF-1 (CXCL12) is expressed in several organs including lung, liver, brain, kidney, skin, and bone marrow, with a probable function during physiological repair mechanisms. Several CXCR4-positive cancers seem to metastasise in an organ-specific
Interleukin 10
TGFβ also upregulates the usually immunosuppressive cytokine interleukin 10, whereas interleukin 10 enhances the expression of TGFβ in a positive feedback circuit.28 Interleukin 10 inhibits antigen presentation, MHC class II expression, and the upregulation of costimulatory molecules CD80 and CD86. Interleukin 10 prevents the production of the Th1-associated cytokines interleukin 2 and interferon-γ from antigen-presenting cells (APCs). Physiologically, interleukin 10 significantly suppresses
Interleukin 2
Interleukin 10 is also an inhibitor of interleukin-2 production in Th2 cells. Interleukin 2 is a growth factor for antigen-stimulated T lymphocytes and is responsible for T-cell clonal expansion after antigen recognition in adaptive immunity. Interleukin 2 is produced primarily by activated CD4+ T cells and by naive CD8+ T cells and DCs.35 Interleukin 2 stimulates proliferation and differentiation of NK cells.36 Activated cytotoxic T cells need interleukin 2 as a growth factor at late stages of
Interaction between interleukin 12, interferon-γ, and HLA-DR
The reciprocal activation of APCs and NK cells via interleukin 12 and interferon-γ is one of the central processes in immunodetection and seems to be negatively affected in patients with cancer. APCs, macrophages, and, mainly, DCs bind antigens in the periphery and transport these antigens to the lymph nodes. In the lymph nodes, APCs present MHC-class-II-associated peptides for recognition by CD4+ lymphocytes. HLA-DR (MHC class II) expression needs stimulation by interferon-γ, which occurs when
Reduced interleukin-12 expression
Interleukin 12 is one of the essential proinflammatory cytokines that stimulates Th1 responses; increased expression of interleukin 12 should occur during a physiological immune reaction.37 This step seems to be negatively affected in many patients with cancer: expression of interleukin 12 seems to be decreased in several cancer types, particularly in late stages with larger and more advanced disease, as described in anaplastic astrocytoma, glioblastoma, paediatric soft-tissue sarcomas,
Interferon-γ
Interleukin 12 is essential for the production of interferon-γ, which in turn has an essential role in MHC expression as a central step of immunodetection. Interferon-γ is the principal macrophage-activating cytokine. The major sources of interferon-γ are CD8+ T cells, CD4+ T cells, and NK cells.40 Activated CD8+ T cells produce interferon-γ after antigen stimulation.41 Secretion of interferon-γ by NK cells and APCs is probably important in early host defence, whereas T lymphocytes become the
HLA-DR expression
Reduced expression of MHC class I and class II impairs immunological tumour recognition. Additionally, HLA-DR antigen expression is crucial for activation of naive CD8+ T cells and is hence essential for a successful adaptive immune reaction against cancer cells.
Markedly diminished HLA-DR expression on monocytes was reported in six cancer types (glioblastoma, lung cancer, pancreatic carcinoma, colorectal cancer, malignant melanoma, and head and neck cancer; table 1). In 12 different unrelated
Interleukin 18
In addition to interleukin 12, production of interferon-γ is influenced by interleukin 18, which is secreted by APCs and a wide range of cell types including activated monocytes, macrophages, T lymphocytes, and NK cells.43 Interleukin 18 is a costimulatory factor for the induction of interleukin-12-mediated interferon-γ production by T-helper cells, and most peripheral CD4+ T cells express the receptor interleukin-18R alpha. Interferon-γ also induces the expression of the antagonistic
TNFα
Macrophages and DCs function as APCs. Macrophages respond to inflammatory stimuli by immediate production of TNFα, interleukin 1, and other chemokines. TNFα and interleukin 1 are described as acute-response cytokines. The principal function of TNFα is to stimulate the activation and recruitment of neutrophils and monocytes to sites of inflammation. TNFα (and also interleukin 1) activates vascular endothelial cells and causes endothelial cells to express adhesion molecules for neutrophils,
Macrophage migration inhibitory factor
Macrophage migration inhibitory factor (MIF) is a rapidly induced immunostimulatory cytokine. MIF is expressed in monocytes, macrophages, T and B lymphocytes, eosinophils, mast cells, basophils, and neutrophils.51 MIF inhibits the migration of macrophages and sustains macrophage viability and hence the inflammatory reaction. Macrophages that do not contain MIF are prone to apoptosis.52 Additionally, findings from an experimental model showed that MIF might be a functional non-cognate ligand for
Interleukin 8
Increased serum concentrations of MIF might be associated with higher interleukin-8 concentrations, another factor that is also induced by TNFα (and interleukin 1).56 Interleukin 8 is a member of the CXC chemokine family and has a role as activator and chemoattractant for neutrophils.
Interleukin 8 is produced by tumour cells of ten different cancer types (NSCLC, breast cancer, colon cancer, gastric cancer, malignant melanoma, pancreatic cancer, malignant glioma, renal-cell carcinoma,
Interleukin 6
A further effect of TNFα and interleukin 1 is the rapid induction of interleukin-6 gene expression particularly in monocytes and macrophages.57 Interleukin 6 is involved in recruitment of neutrophils and promotes the migration and proliferation of T lymphocytes into the affected tissue.58 Resident fibroblasts produce matrix metalloproteinases after interleukin-6 stimulation and degrade the extracellular matrix. Besides the differentiation of B lymphocytes into immunoglobulin-producing plasma
The Th1–Th2–Th17 paradigm
The initial Th1–Th2 paradigm was based on the identification of CD4+ helper-cell subpopulations, termed Th1 and Th2, which produce distinct and opposing patterns of cytokines with immunostimulatory and immunosuppressive functions. After activation, CD4+ T cells of the Th1 lineage secrete interferon-γ, TNFα, interleukin 2, and interleukin 12. Th1-related cytokines are generally regarded as immunostimulatory. Th2-related cytokines inhibit the Th1 responses. Th2 CD4+ T cells express high
Interleukin 23
Another crucial factor needed for the expansion of Th17 cells is interleukin 23, which has an essential structural similarity with interleukin 12: both cytokines share a common subunit p40. Interleukin 12 consists of the subunits p40 and p35, while interleukin 23 is comprised of p40 and a p19 subunit.39, 69 These subunits are predominantly expressed by activated DCs in vivo.70 Whereas interleukin 12 promotes the differentiation of naive T cells into interferon-γ-producing Th1 cells, interleukin
Cytokines and prognosis in cancer
The association between a high serum concentration of interleukin 6 and a negative prognosis was a consistent finding in 16 different cancer types (diffuse large B-cell lymphoma, renal-cell cancer, pancreatic carcinoma, colorectal cancer, gastric cancer, neuroblastoma, metastatic malignant melanoma, non-Hodgkin lymphoma, nasopharyngeal carcinoma, lung cancer, metastatic breast cancer, bladder cancer, advanced gastric cancer, prostate cancer, neck squamous-cell carcinoma, and oesophageal
Present treatment approaches
Even without a comprehensive theory of a uniform immune reaction pattern, several cytokine alterations have been specifically addressed in various experimental treatments. Fresolimumab, a human anti-TGFβ monoclonal antibody, neutralises all active isoforms of TGFβ and was used in a phase 1 study for the treatment of 22 patients with advanced melanoma and renal-cell carcinoma.75 The antisense phosphorothioate oligodeoxynucleotide trabedersen is a specific inhibitor of TGFβ2 biosynthesis and is
Summary of cytokine interactions in cancer
The theoretical evidence that has been established in immunological basic research was used in the present Review to progress from a purely phenomenological clinical description of cytokine interactions in cancer towards an attempted relational and sequential analysis. However, provision of a detailed account of the experimental data that served as a foundation for the interpretation of the clinical findings is beyond the scope of this Review. The result of this translational approach is a
Search strategy and selection criteria
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