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Glenn Dranoff about the author

Department of Medical Oncology, Dana–Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.


The mixture of cytokines that is produced in the tumour microenvironment has an important role in cancer pathogenesis. Cytokines that are released in response to infection, inflammation and immunity can function to inhibit tumour development and progression. Alternatively, cancer cells can respond to host-derived cytokines that promote growth, attenuate apoptosis and facilitate invasion and metastasis. A more detailed understanding of cytokine–tumour-cell interactions provides new opportunities for improving cancer immunotherapy.

Although alterations in tumour suppressors and oncogenes underlie the cell-autonomous defects that are characteristic of cancer, tumours arise and progress within a microenvironment that is replete with healthy, non-transformed cells. Crosstalk between normal and neoplastic cells is increasingly recognized to influence various stages of carcinogenesis1. Early during tumour formation, stromal cells might provide signals that regulate cancer-cell growth and differentiation, whereas later in tumour development, stromal-cell-derived cues can modulate cancer-cell invasion and metastasis2. Proliferating tumour cells can also commandeer existing vasculature or stimulate the generation of new vessels to maintain a robust blood supply3.

In some cases, immune cells constitute an additional, prominent component of the host response to cancer, but their participation in tumour pathogenesis remains incompletely understood. Dense intratumoral lymphocyte infiltrates in early-stage neoplasms are strongly correlated with reduced frequencies of metastasis and improved patient survival in several cancer types4-8. These associations indicate that some host responses can attenuate disease progression9. Alternatively, compelling epidemiological data indicate that diverse forms of chronic inflammation markedly increase the risk of malignant transformation10 and, therefore, that unresolved host immune reactivity can promote tumour development11. In a third scenario, tumour samples, particularly those obtained in the setting of disseminated disease, fail to show immune-cell infiltrates, indicating that these cancers can remain undetected by the immune system12. Collectively, these findings reveal a broad range of possible antitumour responses, each linked with a distinct clinical outcome.

One variable that might prove decisive in moulding the host reaction is the mixture of cytokines that is produced in the tumour microenvironment13. Cytokines are secreted or membrane-bound proteins that regulate the growth, differentiation and activation of immune cells. The cellular alterations that give rise to cancer provoke changes in local cytokine expression. These perturbations stimulate immune-cell infiltrates, which, in turn, release additional cytokines that act in an AUTOCRINE or PARACRINE fashion. Efforts to understand cytokine function during tumour development and progression are complicated by the pleiotropy and apparent redundancy of cytokine action and by the ways in which the overall cytokine environment shapes the effects of individual cytokines14. Notwithstanding these formidable difficulties, loss- and gain-of-function experiments have yielded important insights into the complex associations between cytokines and tumours. In this review, I discuss the emerging evidence that cytokines have a role in tumour formation and show that manipulation of the cytokine balance can be exploited for cancer therapy.

Immune recognition of tumours

The immune system can be broadly divided into innate and adaptive components, with extensive crosstalk between the two (Fig. 1). The innate response includes soluble factors, such as COMPLEMENT PROTEINS, and several cellular effectors, including granulocytes, mast cells, macrophages, dendritic cells (DCs) and natural killer (NK) cells. Innate immunity serves as the first line of defence against infection, as germ-line-encoded pattern-recognition receptors and other cell-surface molecules quickly detect microbial constituents, thereby orchestrating inflammatory reactions15. By contrast, adaptive immunity, mediated by antibodies and CD4+ and CD8+ T cells, is slower to develop. This reflects the requirement for the expansion of rare lymphocytes that harbour somatically rearranged immunoglobulin molecules, or T-cell receptors that are specific for either microbial-derived proteins or processed peptides that are presented by MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) molecules16. NKT cells and T CELLS are cytotoxic T lymphocytes that function at the intersection of innate and adaptive immunity.

Figure 1 | The innate and adaptive immune response.

The innate immune response functions as the first line of defence against infection. It consists of soluble factors, such as complement proteins, and diverse cellular components including granulocytes (basophils, eosinophils and neutrophils), mast cells, macrophages, dendritic cells and natural killer cells. The adaptive immune response is slower to develop, but manifests as increased antigenic specificity and memory. It consists of antibodies, B cells, and CD4+ and CD8+ T lymphocytes. Natural killer T cells and T cells are cytotoxic lymphocytes that straddle the interface of innate and adaptive immunity.

Two main mechanisms are involved in the immune recognition of cancer cells (Fig. 2A). In one pathway, components of innate immunity use pattern-recognition receptors and other cell-surface molecules to directly detect tumour cells. Cancers frequently express families of stress-related genes, such as MICA and MICB, which function as ligands for NKG2D receptors that are expressed by NK cells, other cytotoxic lymphocytes and phagocytes17. NK cells also monitor for the loss of MHC class I molecules from the surface of tumour cells, which commonly occurs during carcinogenesis18. DCs can use CD36 and the v5 integrin to phagocytose apoptotic tumour cells19; moreover, heat-shock proteins that are released from necrotic cancer cells can chaperone tumour-derived peptides for uptake by DCs and macrophages through scavenger receptors or CD91 (Ref. 20).

Figure 2 | Direct and indirect pathways of cancer recognition.

a | Innate immune cells recognize cancers through germ-line-encoded pattern-recognition receptors and other cell-surface molecules. Cancers express various stress-induced genes such as MICA and MICB that trigger NKG2D receptors on natural killer (NK) cells, macrophages and some cytotoxic T lymphocytes (CTLs). NK cells also use a combination of inhibitory and activating receptors such as the killer-cell immunoglobulin-like receptors (KIRs) to detect the loss of major histocompatibility complex (MHC) class I expression on cancers. Dendritic cells (DCs) phagocytose apoptotic tumours through CD36 and v5. Macrophages and DCs also use scavenger receptors and CD91 to ingest heat-shock proteins (HSPs) complexed with tumour-derived peptides that are released from necrotic cancer cells. b | Adaptive immune cells are initially stimulated to recognize cancer cells through cross-priming by DCs. As tumour cells do not express co-stimulatory molecules that are important for T-cell activation, they generally cannot prime cellular responses efficiently. Instead, DCs capture dying tumour cells or debris, migrate to regional lymph nodes and process the tumour-derived material onto CD1D, for presentation to NKT cells (not shown), and MHC class I and class II molecules for presentation to CD4+ and CD8+ T cells. Mature DCs express co-stimulatory molecules such as B7-1 and B7-2 to enhance T-cell activation. DCs secrete IL-12 and IL-18 to promote T helper 1 (TH1) CD4+ T-cell responses and cytotoxic CD8+ T cells. Activated CD4+ T cells and NKT cells express CD40 ligand, which further stimulates DC maturation through CD40 signalling. CD4+ T cells and DCs also help trigger B cells to produce antibodies that are reactive with tumour proteins.

The adaptive immune system usually exploits an indirect pathway — termed CROSS PRIMING — to achieve initial recognition of cancers (Fig. 2B). Tumour cells typically lack the expression of important co-stimulatory molecules, such as B7 family members, that are necessary to directly prime potent T-lymphocyte responses21. By contrast, DCs that have phagocytosed tumour-cell debris process the material for MHC presentation, upregulate expression of co-stimulatory molecules such as B7-1 and B7-2 and migrate to regional lymph nodes to stimulate tumour-specific lymphocytes22. This pathway produces CD4+ and CD8+ T cells that react with the MHC-restricted tumour peptides that are derived from mutated proteins, aberrantly expressed gene products and normal differentiation antigens that are produced by the cancer cells23. CD4+ T cells can also provide help for the production of antibody responses against amplified or mutated tumour-associated gene products24, 25.

Collectively, these findings show that cancer-bearing hosts can frequently mount innate and adaptive antitumour responses. However, the development of clinically evident cancers indicates that these reactions are not always sufficient to preclude disease progression, as tumour cells manage to escape immune recognition and elimination. The mechanisms that underlie this failure in immunity remain to be fully clarified, but are likely to include inefficient cross-priming, regulatory pathways that maintain immune tolerance to host self-antigens, tumour-derived immunosuppressive factors and tumour genomic instability, all of which would allow tumours to grow undetected26. As discussed later, the therapeutic administration of cytokines can prove beneficial in overcoming some of these defects.

Role of cytokines in cancer development

Cytokines are released in response to a diverse range of cellular stresses, including carcinogen-induced injury, infection and inflammation. In these settings, cytokines function to stimulate a host response that is aimed at controlling the cellular stress and minimizing cellular damage. Whereas effective containment of the insult promotes tissue repair, the failure to resolve the injury can lead to persistent cytokine production and to an exacerbation of tissue destruction. As such, host reactions to cellular stress can impact on several stages of cancer formation and progression.

Chemical carcinogens. The characterization of cancer-specific antigens together with the prognostic importance of dense intratumoral lymphocyte infiltrates indicates that some attempt is made by the immune system to impede tumour growth. To delineate a potential role for cytokines in inhibiting tumour formation, several groups examined the susceptibility of immunodeficient mice to chemical carcinogens (Table 1). Schreiber and others demonstrated that, compared with wild-type controls, mice with impaired interferon- (Ifn-) function had an increased susceptibility to the polycyclic hydrocarbon methylcholanthrene, as measured by a higher frequency of tumour formation and a shorter period of tumour latency27-29. IFN-, a cytokine that is produced by T cells, NK cells, NKT cells and, to a lesser extent, DCs and macrophages, was previously shown to mediate pleiotropic effects in the innate and adaptive response to infection30. A comparable sensitivity to carcinogens was detected in mice that are deficient in Ifn-, Ifn- receptor (Ifn-r) or Stat1, a transcription factor that is crucial for Ifn- signalling. Mice that lacked the p40 subunit of interleukin (Il)-12 and Il-23, two cytokines that stimulate Ifn- production, and mice that lacked NKT cells, a key source of Ifn-, also developed more tumours in response to chemical carcinogens than normal mice31.

Table 1 | Roles for endogenous cytokines in tumour pathogenesis*

The mechanisms by which IFN- deficiency promotes increased tumour formation are probably multifactorial and include attenuated control of target-cell growth and apoptosis, increased angiogenesis and impaired wound healing. However, defective cell-mediated immunity also has a crucial role, as IFN- can upregulate MHC class I expression in the tumour and therefore enhance its IMMUNOGENICITY32. Mice that lacked T and B cells — because of a deletion in the Rag2 protein, which is required for the rearrangement of T-cell and B-cell receptors during lymphocyte development — or that lacked important mediators of lymphocyte cytotoxicity such as T cells, perforin or TNF-related apoptosis-inducing ligand (Trail) similarly manifested an increased susceptibility to methycholanthrene treatment32-37. Moreover, tumours from immunodeficient hosts, but not immune competent hosts, were efficiently rejected after transplantation into wild-type animals, revealing an increased sensitivity of the tumours to cell-mediated recognition and cytotoxicity by the immune system of wild-type animals32.

Immunodeficiency and spontaneous tumours. To test whether host immunity could also suppress spon-taneous cancers, several investigators delineated the incidence of tumours in aged immunodeficient mice (Table 1). Smyth and colleagues reported that perforin-knockout and, to a greater extent, perforin/Ifn- double-knockout mice succumbed to disseminated lymphomas38, 39. Analogous to the chemically induced tumours from immunodeficient hosts, these neoplasms were readily eliminated following transplantation into wild-type mice through a mechanism that involved CD8+ T cells. Similarly, mice with compromised cytotoxicity due to defective Fas–Fas-ligand interactions frequently formed B-cell lymphomas40. FAS is a member of the tumour-necrosis-factor family and functions as a death receptor that helps maintain B-cell and T-cell homeostasis41. Schreiber and colleagues established that Rag2/Stat1 double-knockout mice regularly developed adenocarcinomas of the colon, breast and lung, whereas aged Rag2-knockout mice formed intestinal cancers at a lower but significant frequency and aged Stat1-knockout mice occasionally formed breast cancers32. A broader range of tumour types was also detected in Ifn-r/Trp53 double-knockout mice, compared with Trp53-knockout mice27. Although these findings show that spontaneous cancers occur at a high frequency in immunodeficient mice, the mechanisms that underlie tumour formation remain to be clarified.

Chronic infection. We recently demonstrated that granulocyte–macrophage colony-stimulating factor (Gm-csf)/Ifn- double-knockout mice developed diverse haematological and solid neoplasms within a background of chronic infection and inflammation, although wild-type mice did not form tumours within a comparable time frame42. Antimicrobial therapy inhibited both lymphomagenesis and solid-tumour development, which indicated not only that infectious agents could cause tumours, but also that Gm-csf and Ifn- had key roles in suppressing cancers that were triggered by microbes. Similarly, the spontaneous colon carcinomas arising in T-cell-receptor- (Tcr)/Trp53 double-knockout and Rag2/transforming growth factor- (Tgf-) double-knockout mice were inhibited when the animals were reared under germ-free conditions43, 44.

Tumour formation in these systems is consistent with epidemiological studies in humans, which indicate that various congenital and acquired forms of immunodeficiency are associated with a marked increase in cancers that are caused by microbial agents, especially lymphoma, Kaposi's sarcoma and squamous-cell carcinoma of the skin, cervix or anus45. In these pathologies, Epstein–Barr virus, human herpes virus-8 and papilloma virus function directly as transforming agents46.

Microbes contribute to human cancers in seemingly immunocompetent hosts as well; nearly 15% of all human tumours are linked to infections47. Indeed, Helicobacter-pylori-induced gastric carcinoma and hepatitis-B- or hepatitis-C-virus-induced hepatocellular carcinoma are significant causes of cancer death worldwide. In these settings, pathogens can primarily serve as stimulants for ongoing cytokine production and inflammation, resulting in marked tissue damage. Polymorphisms of the IL-1 gene that confer increased expression of this pro-inflammatory cytokine are associated with an increased risk of gastric cancer48. Similarly, a transgenic mouse model of hepatitis B infection showed that Cd4+ and Cd8+ T lymphocytes are essential for the development of hepatocellular carcinoma49. Hepatocyte damage as a consequence of Fas–Fas-ligand interactions is pivotal to transformation in this system50. Cd4+ T cells that are stimulated by cutaneous bacterial flora also promote the evolution of squamous-cell carcinoma in a transgenic mouse model of human papilloma virus infection51. Together, these results illustrate that cytokine imbalances can promote the progression from chronic infection to cancer.

Chronic inflammation. Unresolved inflammation elicits cell turnover in an effort to restore tissue homeostasis, which, together with carcinogen- or phagocyte-induced DNA damage, can eventually culminate in cellular transformation10. In this process, deregulated cytokine production and aberrant cytokine signalling can lead to altered cell growth, differentiation and apoptosis (Table 1). Transgenic mice that constitutively produce Il-15 — a lymphocyte growth factor — succumbed to NKT-cell leukaemias52. Macrophage-migration inhibitory factor (MIF) — a cytokine that modulates the activities of macrophages and lymphocytes — can antagonize p53 function, thereby favouring target-cell survival in foci of chronic inflammation53. In contrast to the protective effects of IFN-, tumour-necrosis factor- (TNF-) and IL-6 contributed to the induction of skin tumours and lymphomas by chemical carcinogens54-56. The invasion and dissemination of breast carcinoma in a transgenic mouse model involved macrophage colony-stimulating factor (M-csf), a key growth and differentiation factor for monocytes/macrophages57. Il-1 was required for the invasion and angiogenesis associated with transplantable tumours58. The development of squamous-cell carcinomas in mice that were transgenic for human papilloma virus depended on bone-marrow-derived cells, which provide matrix metalloproteinase-9, an important cofactor for angiogenesis59. Moreover, the aberrant expression of chemokine receptors allowed tumour cells to subvert the normal signals for cell migration, so fostering metastasis60. In this context, high levels of the chemokine receptors CXCR4 and CCR7 on breast cancer cells were associated with dissemination to various tissues — lymph nodes, lungs, liver and bone marrow — that produced high levels of the specific CHEMOKINES SDF-1 and 6Ckine. Similarly, high levels of the chemokine receptor CCR10 on malignant melanomas can respond to the chemokine CTACK that is expressed in skin.

Collectively, these findings illustrate diverse ways in which tumour cells exploit cytokines and immune cells to favour cancer development and progression. In this scenario, inhibiting host responses might prove therapeutic. The ability of non-steroidal anti-inflammatory agents to reduce tumour formation in several mouse models and in patients at high risk for colon carcinoma supports this idea61, 62.

Cytokine therapies

Systemic administration. As the mixture of cytokines that is present in the tumour microenvironment shapes host immunity, therapeutic manipulation of the cytokine environment constitutes one strategy to stimulate protective responses. Indeed, William Coley's pioneering work at the end of the nineteenth century — in which bacterial extracts were administered as cancer immunotherapy (Coley's toxins) — resulted in marked alterations in cytokine levels and tumour clearance in some of the treated patients (Box 1). Although the toxicities of this approach ultimately proved limiting, probably reflecting the unintended consequences of an elicited cytokine storm that resembled toxic shock, it is noteworthy that some patients with disseminated disease achieved durable clinical benefits63.

In an attempt to retain the therapeutic potential of Coley's toxins and, at the same time, ameliorate the undesirable side effects, subsequent investigators explored the systemic infusion of individual cytokines (Table 2). Perhaps the most effective agent that has been identified so far is IFN-, which evokes antitumour effects in several haematological malignancies and solid tumors64. In malignant melanoma, randomized clinical trials established that IFN- reduces the risk of recurrence following surgical excision of localized lymph-node metastases65, 66. The mechanisms that underlie the antitumour activity of IFN- remain incompletely understood, but might include direct effects on tumour cells in addition to immune stimulation (Box 2).

Table 2 | Cytokines as cancer therapy

The systemic administration of other cytokines can elicit modest clinical benefits (Table 2). The infusion of high doses of IL-2 mediates tumour regression in a minority of patients with renal-cell carcinoma or melanoma67, 68. The precise mechanisms of this therapy remain to be defined, but increased cytotoxicity and alterations in tumour blood flow are probably important. Lower doses of IL-2 are less toxic and can increase the numbers of NK cells69; unfortunately, tumour responses are reduced, possibly because of the expansion of regulatory T cells that, paradoxically, suppress the intended antitumour response70. Although systemic TNF- provokes severe side effects, localized perfusion into limbs that harbour malignant melanoma or sarcoma confers substantial therapeutic benefit71. Systemic Il-12 elicits striking antitumour effects in mouse models, but clinical testing was abruptly curtailed because of unexpected severe toxicities72. Systemic Gm-csf confers some clinical advantages in melanoma, prostate cancer and pulmonary metastases, perhaps through immune stimulation73-75. Finally, although granulocyte colony-stimulating factor (G-CSF) and erythropoietin do not target tumours directly, they are used widely to ameliorate the haematological toxicities of progressive cancer and cytotoxic treatments76, 77.

Overall, the systemic infusion of defined cytokines is associated with significant side effects that bear a certain resemblance to a state of overwhelming infection. Moreover, systemic cytokine administration has achieved only modest therapeutic benefits so far, perhaps reflecting a failure of the approach to recapitulate accurately the paracrine function of cytokines in tissue microenvironments.

Direct tumour injection. In an effort to manipulate cytokine function in a more physiological way, investigators have modified the cytokine environment directly at tumour sites. Forni and colleagues were the first to show that the peritumoral injection of specific cytokines, particularly IL-2, could enhance tumour rejection through a coordinated host reaction composed of neutrophils, eosinophils, macrophages, NK cells and lymphocytes78. In some cases, this destruction engendered systemic immunity that conferred protection against subsequent tumour challenge.

The application of gene-transfer techniques for the stable modification of tumour cells accelerated the screening of a large number of cytokines for their relative abilities to stimulate tumour rejection13. Most investigations involved the ex vivo transduction of tumours with replication-defective viral vectors encoding cytokine genes followed by implantation of the genetically modified tumours into SYNGENEIC mice. An alternative strategy, which generally yielded similar results, explored the intratumoral injection of recombinant viral vectors. In both approaches, animals that rejected the cytokine-secreting tumours were evaluated for the ability to generate protection against subsequent challenges with wild-type tumours (vaccination activity). Although several gene products increased systemic immunity to varying degrees, Gm-csf and Il-12 proved to be the most potent in many tumour models79, 80 (Table 2). IL-12 augmented tumour rejection by promoting T-helper 1 (TH1) responses (which are characterized by robust IFN- production), increasing lymphocyte cytotoxicity and inhibiting angiogenesis81. GM-CSF increased the activation of DCs, macrophages, granulocytes and NKT cells, thereby improving tumour antigen presentation82, 83. GM-CSF-based vaccines generated CD4+ T cells with a broad cytokine profile84. Although T-helper 2 (TH2)-type cytokines, such as IL-4, IL-5, IL-6, IL-10, and IL-13, are generally associated with allergic or parasitic reactions, they can also contribute to tumour rejection by boosting eosinophil function and increasing antibody concentrations84, 85. A multifaceted cellular and humoral reaction might be most likely to overcome the immuno-evasive properties and many apoptotic defects that are intrinsic to cancer cells86 (Fig. 3).

Figure 3 | A coordinated cellular and humoral reaction mediates tumour destruction.

Following stimulation, natural killer (NK) cells can lyse tumours through the perforin/granzyme pathway or apoptosis-inducing ligands such as tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). NK cells secrete interferon- (IFN-), which inhibits tumour-cell proliferation, enhances tumour-cell apoptosis, improves tumour antigen presentation and inhibits angiogenesis. NKT cells also execute cytotoxicity and cytokine production. Cytotoxic CD8+ T cells lyse tumours through death ligands, such as TRAIL, and the perforin/granzyme pathway. CD4+ T cells can differentiate into T helper 1 (TH1) cells that secrete IFN- and TNF- or T helper 2 (TH2) cells that secrete interleukin (IL)-4, IL-5, IL-6, IL-10 and IL-13. The latter cytokines enhance eosinophil function and increase antibody production by B cells. Antibodies to cancer cell-surface molecules can inhibit oncogenic signalling and/or stimulate tumour destruction through engaging Fc receptors on macrophages, granulocytes and NK cells (not shown). Antibodies can further promote tumour antigen presentation by dendritic cells (DCs) through immune-complex formation. Macrophages can lyse tumours through the production of nitric oxide and reactive oxygen species. Tumour blood vessels can also be attacked by lymphocytes and granulocytes.

Cytokine-based vaccines

Numerous pre-clinical studies established the ability of cytokine-secreting tumours to function as cellular vaccines that augment systemic immunity against wild-type tumours. Several strategies have been pursued to translate this form of immunotherapy into clinical testing. One approach uses autologous tumour cells, as experiments in mouse models indicate that tumour-specific antigens might be the most potent for cancer vaccination. The logistical challenges in preparing patient-specific therapies, however, have motivated the exploration of ALLOGENEIC tumour cell lines. These express shared tumour antigens and can be phagocytosed and processed by host DCs through cross-priming. Using these approaches, many cytokines have been introduced into early-stage clinical trials, including GM-CSF, IL-2, IL-4, IL-6, IL-7, IL-12, IFN- and lymphotactin87 (Table 2).

Clinical development of GM-CSF-based vaccines. To test whether GM-CSF-based vaccines stimulated tumour immunity in humans, we conducted a Phase I clinical trial in patients with metastatic melanoma88. In the study, surgically excised tumours were processed to a single-cell suspension, transduced with replication defective retroviruses expressing GM-CSF, irradiated and used to immunize patients with metastatic melanoma. Autologous tumour-cell vaccines were administered at weekly to monthly intervals into normal skin — alternating between the limbs and abdomen — and were placed distant from sites of known metastases to avoid any local immunosuppressive effects that might compromise immune priming. Vaccination sites showed infiltration of mature DCs, macrophages and granulocytes (Fig. 4). Whereas metastatic lesions that were resected before vaccination were minimally infiltrated with cells of the immune system in all cases, metastatic lesions that were resected after vaccination were densely infiltrated with CD4+ and CD8+ T lymphocytes and B cells. As a consequence, the resected lesions showed extensive tumour necrosis (at least 80%), fibrosis and OEDEMA in 11 of 16 patients examined. These immune reactions were directed, at least in part, towards the melanoma inhibitor of apoptosis protein (ML-IAP), the ATP6S1 subunit of the vacuolar-ATPase complex and the putative opioid growth factor receptor OGFR, as measured by the development of antibodies or T-cell responses89-91. Additionally, four of the sixteen patients manifested the selective destruction of the tumour vasculature by activated lymphocytes, eosinophils and neutrophils.

Figure 4 | GM-CSF-secreting tumour-cell vaccines and CTLA-4 antibody blockade show synergistic antitumour effects.

Vaccination with irradiated tumour cells that are engineered to secrete granulocyte–marcrophage colony-stimulating factor (GM-CSF) stimulates infiltration of dendritic cells (DCs), macrophages and granulocytes at the immunization site. This coordinated cellular reaction promotes the efficient phagocytosis of tumour debris by DCs. G further induces DCs to mature and migrate to regional lymph nodes to prime tumour-specific T and B cells. Activated T cells then upregulate surface cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), which, following engagement by B7 molecules, signals to limit T-cell expansion and cytokine production. CTLA-4 antibody blockade attenuates this inhibition and thereby augments T-cell proliferation and effector functions. CTLA-4 antibody blockade can also inhibit regulatory T cells (which constitutively express surface CTLA-4) and thereby promote the expansion of tumour-specific memory T cells.

Although this Phase I trial in malignant melanoma and similar studies in renal-cell carcinoma and prostate carcinoma established the biological activity and safety of GM-CSF-based tumour-cell vaccines92-94, the use of retroviral vectors that are derived from murine leukaemia virus to accomplish efficient gene transfer presents a formidable logistical hurdle to more extensive clinical evaluation. These vectors require target-cell replication for infection, necessitating the establishment of primary tumour-cell cultures. One approach to simplifying the development of vaccines involves the application of adenoviral vectors, which readily infect resting target cells and are associated with minimal toxicities when used ex vivo95. This strategy proved feasible and biologically active for patients with advanced non-small-cell lung carcinoma96. The use of a cell line that stably expresses GM-CSF admixed with irradiated autologous tumours is yet a further simplification that has entered Phase I testing97. Another variation involves the engineering of allogeneic cancer cell lines to secrete GM-CSF. Immunization with allogeneic pancreatic adenocarcinoma cell lines that were transduced with a GM-CSF expression vector increased tumour immunity in patients with advanced pancreatic carcinoma98.

CTLA-4 antibody blockade. Although most vaccinated patients showed increased cancer immunity in these studies, nearly all eventually succumbed to progressive disease. One mechanism that might restrain the therapeutic potency of cancer vaccines is the attenuation of T-cell function by cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4; Ref. 99; Fig. 4). Following engagement by B7-1 or B7-2, CTLA-4 signalling in activated T cells induces cell-cycle arrest and diminished cytokine production100, 101. Regulatory T cells, a key population that controls effector T cells and helps maintain tolerance to self antigens, also constitutively express surface CTLA-4 (Ref. 102). Allison and colleagues demonstrated that administering an antibody that transiently inhibits CTLA-4 function markedly increased the antitumour effects of GM-CSF-secreting tumour vaccines in several poorly immunogenic mouse models, albeit with the loss of tolerance to normal differentiation antigens103, 104. The potential for severe toxicities with prolonged CTLA-4 blockade, however, was indicated by the development of a fatal lymphoproliferative disease in young CTLA-4-deficient mice105, 106.

Rosenberg and colleagues tested serial infusions of a human monoclonal antibody against CTLA-4 (MDX-CTLA4) together with melanosomal antigen-derived peptide vaccines in 14 patients with metastatic melanoma107. Although three individuals showed tumour responses, six patients developed serious autoimmune disorders that included ENTEROCOLITIS, hepatitis, dermatitis and HYPOPHYSITIS. These findings delineate a crucial role for CTLA-4 in maintaining immune tolerance in humans but also indicate a potential therapeutic benefit for the approach. To determine whether CTLA-4 antibody blockade could elicit antitumour effects without inducing serious autoimmune toxicities, we infused MDX-CTLA-4 into 9 patients with metastatic melanoma or patients with ovarian carcinoma108 who had been previously vaccinated with GM-CSF-secreting tumour cells. MDX-CTLA-4 induced tumour destruction and immune infiltrates in 5/5 patients who had been previously vaccinated with irradiated, autologous GM-CSF-secreting tumour cells; by contrast, the antibody did not elicit tumour necrosis in 4 of 4 metastatic melanoma patients who had been previously immunized with other types of vaccines. MDX-CTLA-4 did not provoke any serious toxicity in this setting, although mild autoimmune reactions were observed, including transient skin rashes and the development of low titres of autoantibodies. These results indicate that CTLA-4 antibody blockade can preferentially augment antitumour memory responses in some previously vaccinated patients with cancer. The work also provides a foundation for exploring various sequential and concurrent immunotherapies, in which manipulations that are aimed at priming antitumour reactions are mixed with strategies that attenuate immune-regulatory circuits.

Concluding comments

Recent investigations of the host antitumour response have revealed a previously unappreciated complexity of cancer-cell/immune-cell cross-talk. Studies of cytokine-deficient mice have revealed dual roles for the immune system in suppressing and promoting cancer formation. In these systems, the interplay of chronic infection, inflammation and cancer immunity helps determine the outcome of the host response. Future work should aim at characterizing cytokine pathways in patients with cancer to delineate whether comparable alterations of cytokine function contribute to tumour formation in humans. If such associations could be established, it might become possible to prospectively identify individuals at high risk for cancer. Therapeutic manipulations that are aimed at restoring defective cytokine function or attenuating excessive cytokine action in these subjects might reduce the rate of tumour development.

The dual role of immunity in cancer pathogenesis further implies that immunotherapies for established tumours should target several pathways. Combination approaches that both stimulate protective host responses and inhibit immune subversion tactics are likely to prove most efficacious. Although the safety and toxicities of these strategies must be initially determined in patients with disseminated disease, the most promising approaches should be rapidly advanced to clinical testing in patients with early-stage cancer. This setting presents a more favorable opportunity to augment host responses and, in so doing, achieve an optimal cytokine balance.


Box 1 | Coley's toxins

Towards the end of the nineteenth century, William B. Coley, a surgeon in New York, observed that some patients with cancer who recovered from bacterial infections of the skin — caused by Streptococcus pyogenes — also experienced tumour regression. To explore whether this association was causal, Coley deliberately injected live S. pyogenes into the skin of patients with advanced cancer. A severe local infection with high fevers ensued, but after the illness subsided, the patient experienced marked tumour regression and prolonged survival. As this approach was associated with significant toxicity, Coley later explored the use of bacterial extracts that were derived from a mixture of inactivated S. pyogenes and Serratia marcesens. The detailed clinical reports of many patients who experienced durable tumour regressions in response to the bacterial extracts were collated and reported after Coley's death by his daughter, Helen Coley Nauts63. Her careful scholarship led to a broader appreciation of the connections between the immune system and cancer. Although Coley's toxins did not become a standard cancer therapy, the instillation of the mycobacteria Bacillus Calmette-Guérin (BCG) into the bladder of patients with early-stage carcinoma was shown to be highly efficacious and is still used as a treatment for bladder cancer109.

Box 2 | Interferon-

Many clinical trials have established the ability of interferon- (IFN-) to induce haematological responses and prolong the survival of patients with chronic myelogenous leukaemia (CML), a malignancy of pluripotent haematopoietic stem cells64. IFN- can modulate both the tumour cells and the immune system to achieve clinical benefits. Interferon-consensus-sequence-binding protein (ICSBP) is a transcription factor that helps to regulate the expression of many interferon-stimulated genes110. Icsbp-knockout mice develop a CML-like syndrome111, and the enforced expression of Bcr–Abl — a chimeric gene found in human CML cells that is the result of the (9;22) chromosomal translocation — in mouse cells leads to a CML-like disease that is associated with downregulated Icsbp expression112. In addition, Icsbp-knockout mice show marked decreases in plasmacytoid DCs, a principal in vivo source of IFN-113. Together, these findings raise the possibility that IFN- deficiency can contribute to CML pathogenesis. Consistent with this idea, most CML samples from untreated patients have impaired ICSBP levels, whereas IFN- therapy substantially increased ICSBP expression114. IFN- treatment might further sensitize leukaemia cells to p53-mediated apoptosis115. Patients who responded to IFN- therapy also generated high-affinity CD8+ T cells that specifically recognize CML cells116, 117.



Cancer.gov: anal cancer | breast cancer | cervical cancer | chronic myelogenous leukaemia | colon cancer | gastric cancer | Kaposi's sarcoma | lung cancer | lymphoma | melanoma | ovarian cancer | prostate cancer | skin cancer

LocusLink: 6Ckine | ATP6S1 | CCR10 | CCR7 | CD36 | CD91 | CTACK | CTLA-4 | CXCR4 | erythropoietin | G-CSF | Gm-csf | Ifn- | Ifn-r | IL-1 | IL-2 | IL-4 | IL-5 | IL-6 | IL-7 | IL-10 | Il-12 | IL-13 | IL-15 | IL-23 | M-csf | MICA | MICB | MIF | ML-IAP | NKG2D | OGFR | perforin | Rag2 | SDF-1 | Tgf- | TNF- | Trail



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