Biologic effects of IL-1

IL-1 can increase the expression of itself as well as many other cytokines (including IL-1RA), cytokine receptors (including IL-2, IL-3, IL-5, granulocyte macrophage-colony-stimulating factor [GM-CSF], and c-kit), inflammatory mediators (such as cyclooxygenase and inducible nitric oxide synthase), hepatic acute-phase reactants, growth factors, clotting factors, neuropeptides, lipid-related genes, extracellular matrix molecules, and oncogenes (e.g., c-jun, cabl, c-fms, c-myc, and c-fos).¹ Data suggest that an inflammatory component is present in the microenvironment of most neoplastic tissues, including those not causally related to an obvious inflammatory process. Thus, as a proinflammatory cytokine, IL-1 may also be a major proangiogenic stimulus of both physiological and pathological angiogeneses.

The IL-1 family has been implicated in the function and the dysfunction of virtually every human organ system. Indeed, increased IL-1 production has been reported in patients with infections (viral, bacterial, fungal, and parasitic), intravascular coagulation, cancer (both solid tumors and hematologic malignancies), Alzheimer’s disease, autoimmune disorders, trauma, ischemic diseases, pancreatitis, graft-versus-host disease, transplant rejection, and in healthy subjects after exercise.¹

It has been suggested that the balance between IL-1 and its naturally occurring antagonists is most relevant to illness.³ This balance may be altered in different ways, depending on the disease. In AML, IL-10 is spontaneously expressed, but IL-1RA gene expression is suppressed even when stimulated with GM-CSF.^{4, 5} CML patients with advanced disease and poor survival have suppressed IL-1RA accompanied by high IL-1β.⁶ In AML and CML patients, IL-1β acts as an autocrine growth factor; exposure to molecules that decrease the activity of IL-1 suppresses leukemic proliferation.^{7, 8} Constitutive production of IL-lα, IL-1β, and/or IL-1RA in solid tumors (melanomas, hepatoblastoma, sarcomas, squamous cell carcinomas, transitional cell cancers, and ovarian carcinomas) has been described and may, in some cases, contribute to metastatic potential. However, the relationship between IL-1 and tumor growth is complex.

IL-1 in the clinic

IL-lα and IL-1β have both been administered in clinical cancer trials.¹ In general, the acute toxicities of both isoforms were greater after intravenous than subcutaneous injection. Subcutaneous injection was associated with significant local pain, erythema, and swelling. Dose-related chills and fever were observed in nearly all patients, and even a 1 ng/kg dose was pyrogenic. Nearly all patients receiving intravenous IL-1 at doses of 100 ng/kg or greater were experienced significant hypotension, probably because of induction of nitric oxide.

IL-1 infusion into humans significantly increased circulating IL-6 levels and resulted in a rise in leukocyte counts, even at doses as low as 1 or 2 ng/kg. Increases in platelets, peripheral monocyte count, and phorbol-induced superoxide production were also observed in patients with normal marrow reserves. In contrast to the results in patients with good marrow function, patients with aplastic anemia treated with five daily doses of IL-lα (30–100 ng/kg) had no increases in peripheral blood counts or bone marrow cellularity.⁹ However, after chemotherapy, two doses of IL-10 significantly shortened the duration of neutropenia,¹⁰ and IL-lα (5 days) significantly reduced thrombocytopenia.¹¹ Overall, the benefits of IL-1 therapy were compromised by its toxicity.

Biologic activities of IL-2

IL-2 primarily acts as a T-cell growth factor, but B cells, natural killer (NK) cells, and lymphokine-activated killer (LAK) cells are also responsive to this cytokine. Following binding of IL-2 with the trimeric receptor complex, internalization occurs and cell-cycle progression is induced in association with the expression of a defined series of genes.¹³ A second functional response occurs through the IL-2β, dimeric receptor, also known as the intermediate affinity dimeric complex (kDa, 10⁻⁹), and involves the differentiation of several subclasses of lymphocytes into LAK cells.¹⁴ This response occurs in patients with cancer who receive IL-2^{15, 16} and was originally considered to be a critical part of the anticancer effect of IL-2.

IL-2 in the clinic

IL-2 has had a profound impact on the development of cancer immunotherapy. The administration of IL-2 and the adoptive transfer of antitumor T cells grown in IL-2 represented the first effective immunotherapies for cancer in humans.¹⁷ Since 1992, numerous clinical trials using high-dose IL-2 (HD IL-2) have delivered a remarkably consistent 7% complete response rate in two advanced cancer types, renal cell carcinoma (RCC) and malignant melanoma.^18–22 Many of these complete responses have been durable beyond 10 years. HD IL-2 likely enhances the immune response against cancer cells. Its anticancer activity is strongly related to its ability to act as a growth factor for T lymphocytes, its capacity to stimulate antigen-independent NK cells and LAK cells, and its ability to increase lymphocytes at the site of malignancy. The significant adverse effects of HD IL-2 are largely a result of severe vasodilation and capillary leak syndrome, and include hypotension, arrhythmias, and liver and renal toxicities. Its administration requires an inpatient intensive care-like setting, thus it is recommended in patients with few comorbidities and an excellent performance status. There is a 1–2% risk of mortality with IL-2, which highlights the importance of choosing a well-suited patient for this treatment modality.²³

Historically, HD IL-2 was first used in a combinational biochemotherapy (BCT) setting, usually involving cisplatin, vinblastine, and dacarbazine (CVD) or cisplatin, vinblastine, and temozolomide (CVT), plus the biologic agents IFN α and IL-2. However, a modest increase in survival came with a substantial increase in toxicity.²⁴ More recently, as drugs such as ipilimumab demonstrate durable responses, the role of HD IL-2 as a single agent is becoming more controversial. One rational approach is to combine the two approved immunotherapies for stage IV melanoma, ipilimumab and IL-2. No data are currently available regarding the correct sequencing of immunotherapies. Some melanoma experts believe that IL-2 is best used very early on in therapy when subjects have more limited disease (M1a disease) and good performance status. A small study has indicated that there may be a higher response rate (47%) in patients with NRAS-mutant melanoma, but further validation of this finding is needed.²⁵ A 2005 study in 36 patients with advanced melanomawho received a combination of ipilimumab (0.1–3 mg/kg every 3 weeks) and IL-2 demonstrated an overall response rate of 22%.²⁶ Studies evaluating the role of ipilimumab with adoptive cell therapy are ongoing. Another approach to extend or enhance the efficacy of HD IL-2 or ipilimumab therapy is to combine immunotherapy with BRAF inhibitors for treatment of patients with BRAFV600-mutant advanced melanoma.²⁷ Preclinical studies showed an increase in melanoma antigen expression and the number of tumor-infiltrating lymphocytes in tumor biopsies after BRAF inhibitor therapy, which correlated with a reduction in tumor size and an increase in necrosis.^{28, 29} Current efforts are examining tumor biopsies from patients receiving vemurafenib to assess the mechanisms and kinetics of T-cell accumulation within tumors and characterize the specificity and function of immune infiltrating cells to design more successful combination treatments of BRAF inhibitor and immunotherapy regimens.

Biologic properties of IL-3

In vitro, IL-3, in combination with other cytokines, such as stem cell factor (SCF), IL-6, IL-1, GM-CSF, GM-CSF, erythropoietin (EPO), or thrombopoietin (TPO), induces the proliferation of colony-forming unit (CFU)-GM, CFU-Eo, CFU-Baso, BFU-E, and CFU-GEMM in semisolid medium and stimulates the proliferation of purified CD34+ cells in suspension culture.³¹ Indeed, IL-3 is combined with other cytokines, in particular SCF, IL-6, IL-1, FL, G-CSF (granulocyte colony-stimulating factor), and/or EPO, in almost all protocols to expand hematopoietic stem and progenitor cells in vitro.

IL-3 in the clinic

IL-3 has been used in a variety of clinical trials; peripheral blood stem cell mobilization, postchemotherapy and transplantation, and bone marrow failure states. The majority of studies show only modest effects of IL-3 by itself but significant salutary effects in conjunction with other growth factors. For instance, in mobilization studies, treatment with IL-3 did not mobilize by itself but significantly potentiated G-CSF-induced yield of all progenitor cell types used to restore hematopoiesis after high-dose chemotherapy. After transplantation, the combination of IL-3 and GM-CSF proved more efficient to support bone marrow engraftment than IL-3 or GM-CSF alone. The combination of IL-3 and GM-CSF was more efficient than G-CSF for supporting platelet recovery but was of similar benefit for the reconstitution of myelopoiesis. Following chemotherapy, IL-3 was found to attenuate neutropenia and/or thrombocytopenia in some but not all clinical studies.

Biologic activities of IL-4 and IL-13

IL-13 elicits many, but not all, of the biologic actions of IL-4. IL-4 is, however, distinguished from IL-13 by its T-cell growth factor activity and its ability to drive differentiation of Th0 precursors toward the Th2 lineage. Th2 cells secrete IL-4 and IL-5 and lead to a preferential stimulation of humoral immunity. In contrast, Th1 cells, which produce IL-2 and IFN-γ, lead to a preferential stimulation of cellular immunity.

IL-4 and IL-13 possess potent antitumor activity in vivo in mice.⁴¹ They can inhibit the proliferation of some human cancer cell lines in vitro and in vivo in nude mice. A similar antiproliferative effect of IL-13 on human breast cancer cells has been described. Moreover, a chimeric protein composed of IL-13 and a truncated form of Pseudomonas exotoxin A exhibits specific cytotoxic activity toward human RCC but not against normal hemopoietic cells.⁴²

Clinical trials of IL-4

Despite the preclinical promise of IL-4, to date, clinical trials in humans demonstrated that although the molecule is safe and nontoxic, only sporadic antitumor activity is observed in a variety of cancers, including melanoma, lung cancer, and AIDS-related Kaposi’s sarcoma.^43–45

Biologic activities of IL-6

IL-6 affects the hypothalamic-pituitary axis, bone resorption, and both the humoral and cellular arms of the immune system^49–53 and is a potent and essential factor for the normal development and function of both B and T lymphocytes.⁵⁴ IL-6 is also involved in the differentiation of myeloid leukemic cell lines into macrophages, megakaryocyte maturation, neural differentiation, and osteoclast development. As a major inducer of acute-phase protein synthesis in hepatocytes,⁵⁵ this cytokine may play a role in the pathogenesis of sepsis.

IL-6 acts as a growth factor for myeloma/plasmacytoma, keratinocytes, mesangial cells, RCC, and Kaposi sarcoma and promotes the growth of hematopoietic stem cells. On the other hand, IL-6 inhibits the growth of myeloid leukemic cell lines and certain carcinoma cell lines. Significant correlations between serum IL-6 activity and serum levels of acute-phase proteins have been demonstrated in a variety of inflammatory conditions. IL-6 has been implicated as a mediator of B symptoms in lymphoma.⁵⁶ Elevated serum IL-6 levels have also been associated with an adverse prognosis in both Hodgkin lymphoma and non-Hodgkin lymphoma (NHL).^57–60 In diffuse large-cell lymphoma, IL-6 levels were found to be the single most important independent prognostic factor selected in multivariate analysis for predicting complete remission rate and relapse-free survival.⁵⁸ IL-6 levels may also be exploitable as a prognostic factor in RCC and multiple myeloma (MM), and high levels are observed in prostate and ovarian cancers. IL-6 probably also plays an etiologic role in the systemic manifestations of the lymphoproliferative disorder Castleman’s disease.⁶¹ High IL-6 levels are also an adverse prognostic factor in pancreatic cancer.⁶²

IL-6 in the clinic

In patients undergoing chemotherapy or autologous transplantation, IL-6 has minimal to no platelet-enhancing activity at tolerable doses. Toxicity includes fever and anemia.^63–65 IL-6 has also been tested as an antitumor agent in melanoma and RCC. Response rates have been low (<15%).⁵⁵ Because high levels of IL-6 correlate with an adverse outcome in many cancers and function as an autocrine/paracrine growth factor in some tumors, clinical studies of an IL-6 inhibitor may be worthwhile.

IL-6 is one of the most ubiquitously deregulated cytokines in cancer, and increased levels of IL-6 have been observed in virtually every tumor studied. Preclinical and translational findings support a role for IL-6 in diverse malignancies, including breast, lung, colorectal, ovarian, prostate, pancreatic cancers, MM, glioma, melanoma, RCC, leukemia, lymphoma, and Castleman’s disease, and provide a biologic rationale for targeted therapeutic investigations. Various compounds antagonize IL-6 production, including corticosteroids, nonsteroidal anti-inflammatory agents, estrogens, and cytokines. Targeted biologic therapies include IL-6 conjugated toxins and monoclonal antibodies directed against IL-6 and its receptor. As an example, a chimeric murine antihuman IL-6 antibody, CNTO 328, has been used in a phase 1 trial in subjects with B-cell NHL, MM, and Castleman’s disease.⁶⁶ The treatment resulted in tumor response and disease control, especially in Castleman’s disease, where striking responses have been seen.⁶⁷

Biologic activities of IL-7/IL-7 receptor

While most single cytokine knockout mice show relatively normal B- and T-cell compartments, indicating that many cytokine functions are redundant, IL-7-deficient mice present with striking lymphocyte depletion in both the thymus and bone marrow. Collectively, these genetic experiments identify clearly distinct in vivo roles for various lymphoid factors. IL-2 and IL-4 function by influencing mature lymphocyte populations during immune responses, whereas IL-7 plays a singularly dominant role for the production and expansion of lymphocytes. The upregulation of IL-7R occurs at the stage of the clonogenic common lymphoid progenitor that can give rise to all lymphoid lineages at a single-cell level.⁷⁴ There are at least three principal means by which IL-7R-mediated signals act in lymphocyte development: enhancement of proliferation, triggering of lineage-specific developmental programs, and maintenance of viability of appropriately selected cells.

High IL-7 levels are found in states of T-cell depletion and may, therefore, play a role in promoting T-cell expansion.⁷⁵ High levels of IL-7 are also found in CLL and Burkitt lymphoma, and transgenic mice overexpressing the IL-7 gene show dramatic changes in lymphocyte development, which, in some instances, can result in the formation of lymphoid tumors.⁷⁶

Biologic activity of IL-8

The chemotactic agents generated by inflammatory stimuli recruit circulating leukocytes, in particular neutrophils, for defensive purposes and direct them to injury sites. Among the neutrophil-affecting chemokines, IL-8 is one of the most potent.⁸¹ On exposure to a chemokine, neutrophils are activated, and within seconds, their shapes change. The process of shape change is crucial. It is modulated by perturbations of cellular integrins and the actin cytoskeleton. The activation and upregulation of integrins also permits the adherence of neutrophils to the endothelial cells of the vessel wall, to allow for subsequent migration into the tissues. Leukocytes follow the IL-8 concentration gradient and accumulate at the location of elevated concentration. These processes play a fundamental role in the host defense as activated leukocytes act to kill and engulf invading bacteria at the site of injury.

IL-8 can induce tumor growth, an effect attributed to its angiogenic activity. On the one hand, the administration of anti-IL-8 to SCID mice bearing xenografts of IL-8-expressing human lung cancer has been shown to have beneficial effects.⁸² On the other hand, antitumor effects of IL-8 have also been reported. Of interest in this regard is the fact that increased levels of IL-8 have been discerned in lung carcinomas and in melanomas. IL-8 may be a growth factor for pancreatic cancer and for melanoma.⁷⁸ In melanomas, IL-8 levels correlate with the growth and metastatic potential of the tumor cells, and exposure of the cells to IFN (an agent with known antitumor activity in melanoma) decreases IL-8 levels and cancer cell proliferation.⁸³ Blocking IL-8 or IL-8R has been suggested as a therapeutic strategy.⁷⁸

Biologic activities of IL-9

Cellular elements responsive to IL-9 include erythroid progenitors, human T cells, B cells, fetal thymocytes, thymic lymphomas, and immature neuronal cell lines.⁸⁴

IL-9 can support the clonogenic maturation of erythroid progenitors in the presence of EPO. In contrast, granulocyte or macrophage colony formation (CFU-GM, CFU-G, or CFU-M) is usually not influenced by IL-9. IL-9 is more effective on fetal than adult progenitors and in cells that are activated. In addition to its proliferative activity, IL-9 also seems to be a potent regulator of mast cell effector molecules.

There is an interesting paradox between the unresponsiveness of normal T cells to IL-9 and the potent activity of this molecule on lymphoma cells. This contrast is illustrated by the observation that murine T cells acquire the ability to respond to IL-9 after a long period of in vitro culture, while they simultaneously acquire characteristics of tumor cell lines. Observations made with transgenic mice also demonstrate the oncogenic potential of dysregulated IL-9 production as 5–10% of mice that overexpress this cytokine develop lymphoblastic lymphomas.⁸⁵ In line with these data, constitutive IL-9 production by human Hodgkin lymphomas and large-cell anaplastic lymphomas has now been clearly documented.⁸⁴ Even so, the pathophysiologic role of IL-9 remains elusive.

Biologic activities of IL-10

IL-10 inhibits the synthesis of Th1-derived cytokines, including IL-2, IFN-γ, GM-CSF, and lymphotoxin and of monocyte-derived IL-1α and β, IL-6, IL-8, TNF-α, GM-CSF, and G-CSF. Exogenous IL-10 can also suppress expression of IL-10.⁸⁷ At the same time, IL-10 induces the synthesis of the IL-1 receptor antagonist by macrophages. IL-10 also suppresses the CD28 costimulatory pathway and hence acts as a decisive mechanism in determining if a T cell will contribute to an immune response or become anergic.

From the molecular standpoint, IL-10 suppresses cytokine expression at a transcriptional and posttranscriptional level.⁸⁹ Both these mechanisms appear to require new protein synthesis. At a cellular level, Th1 cytokines synthesis inhibition is mediated indirectly through the effect of IL-10 on APC, as suppression occurs when macrophages, but not B cells, are used as APC.⁹⁰

In the presence of monocytes/macrophages, IL-10 inhibits proliferation of resting T cells, including Th0, Th1, and Th2 CD4+ T-cell clones. This inhibition can only be partially reversed by high concentrations of IL-2, suggesting that the reduced proliferation is only partially a reflection of reduced IL-2 production. IL-10 can also enhance the cytotoxic activity of CD8+ T cells. All these effects support an important role of IL-10 in regulating inflammatory responses. In contrast to the inhibitory effects on other lineages, IL-10 has a stimulatory effect on B cells and mast cells.⁹¹ For instance, IL-10 strongly stimulates proliferation and differentiation of activated B cells.

The role of IL-10 in cancer should be considered within the frame of a highly complex biological puzzle. It is known that IL-10 can have pleiotropic effects on adaptive and innate immunity cell mediators. Although several studies show that IL-10 can actively mediate immune suppression, some experimental models describe relatively opposite conclusions. Recent data on the relationship between IL-10 and anticancer immunity support an effective immune attack against malignant cells, which challenges the common belief that IL-10 acts as an immunosuppressive factor promoting tumor immune escape.

Biologic activities of IL-11

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