Clin Exp Med (2011) 11:199–210 DOI 10.1007/s10238-010-0120-7
REVIEW ARTICLE
Lymphocyte subpopulation and dendritic cell phenotyping during antineoplastic therapy in human solid tumors Sara Mariucci • Bianca Rovati • Mariangela Manzoni Matteo Giovanni Della Porta • Giuditta Comolli • Sara Delfanti • Marco Danova
•
Received: 28 May 2010 / Accepted: 29 October 2010 / Published online: 16 December 2010 Ó Springer-Verlag 2010
Abstract Patients with cancer show variable levels of immunosuppression at the time of the presentation, and cytotoxic antineoplastic therapy is the primary contributor to the clinical immunodeficiency often observed during the course of the disease. In both hematological and solid tumors, this phenomenon is primarily related to the T-cell depletion associated with inhibition of dendritic cell ability to induce both primary and secondary T- and B-cell responses. Complete restoration of immunocompetence following antineoplastic therapy implicates the progressive recovery of various cell subpopulations, and it is a complex process that also depends on the type, the dose, the scheduling, and the associations of the employed drugs. In the era of target therapies, several antiangiogenic drugs are increasingly used in combination with standard chemotherapy in the treatment of advanced solid tumors. Their clinical efficacy has been recently related not only to the
S. Mariucci (&) B. Rovati S.C. Oncologia Medica, Laboratorio di Citofluorimetria e Terapie Cellulari, Fondazione IRCCS Policlinico San Matteo e Universita` di Pavia, Viale Golgi, 19, 27100 Pavia, Italy e-mail:
[email protected];
[email protected] M. Manzoni S. Delfanti M. Danova S.C. Oncologia Medica, Fondazione IRCCS Policlinico San Matteo e Universita` di Pavia, Viale Golgi, 19, 27100 Pavia, Italy M. G. Della Porta Istituto di Ematologia, Fondazione IRCCS Policlinico San Matteo e Universita` di Pavia, Viale Golgi, 19, 27100 Pavia, Italy G. Comolli S.C. Virologia e Microbiologia, Laboratori Sperimentali di Ricerca, Area Biotecnologie, Fondazione IRCCS Policlinico San Matteo e Universita` di Pavia, Viale Golgi, 19, 27100 Pavia, Italy
specific antiangiogenic properties but also to an indirect hypothetical effect on the host immune system. In the present work, we have reviewed the most recent information regarding (1) the capacity of standard antineoplastic therapy to induce and maintain an immunodeficiency in patients with solid tumors and (2) the influence of the antiangiogenic treatment in association with standard chemotherapy on lymphocyte and dendritic cell subsets and the possible resulting additional antitumor mechanism. Keywords Lymphocyte subsets Dendritic cells Antineoplastic therapy Angiogenesis Solid tumors
Introduction Standard anticancer therapeutic modalities like chemotherapy evoke host’s reactions that include involvement of the immune system [1]. Despite advances in chemotherapy, most patients with cancer that has metastasized will succumb to the disease within 2 years of diagnosis. In an effort to improve survival, new therapeutic approach focusing on the molecular mechanisms that mediate tumor cell growth or survival has gained attention [2]. In recent years, considerable attention has been paid to newer agents that focus on certain cell receptors known as target therapies for their ability to bind to specific receptors on cancer cells and inhibit cellular pathways, which may lead to apoptosis, or cell death [3, 4]. The molecular targets for these new drugs are located on the cell surface, in intracellular signaling pathways, in the cell nucleus, and on tumor and peri-tumor cell vessels. Among the drugs currently proposed for target therapy, antiangiogenic drugs act by blocking vascular endothelial growth factor (VEGF) and/or its signaling pathway [5].
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Lymphocyte subsets and dendritic cells in human tumors T and B lymphocytes Significant advances in our knowledge on the relationship between the immune system and cancer have come from research on subpopulations of T lymphocytes and natural killer (NK) cells. In terms of both phenotype (markers) and function, non-activated T-lymphocyte subsets, naı¨ve cells responsible for central memory, without direct cytotoxic activity and memory T cells with effector functions that are very important for control tumor growth have been identified [6]. T cells develop in the thymus from a common lymphoid progenitor and are defined by expression of a T-cell receptor (TCR) that is responsible for recognizing antigens presented by the major histocompatibility complex (MHC) family of genes. T cells are classically divided into either CD8? cytotoxic lymphocytes or CD4? T helper (Th) cells that recognize peptides presented by MHCI or MHCII, respectively. Th cells are further divided into interferon (IFN)-c and tumor necrosis factor (TNF)-a expressing Th1 cells and interleukin (IL)-4, IL-5 and IL-13 expressing Th2 cells. A range of additional subtypes of T-cell compartment was identified by T follicular helper cells (TFH), IL-17expressing Th cells (Th17), and regulatory T cells (Tregs). Paralleling these subtypes in the CD4? T-cell compartment, type 1, type 2, and type 17 CD8? T cells (Tc1, Tc2, Tc17), as well as regulatory CD8? cells, have all been described [7]. CD4 and CD8 T cells are the principal helper and effector cells, respectively, of adaptive cellular immunity, and many immunotherapy strategies are aimed at activating these cells to promote tumor cell destruction and long-term immune memory against recurrence of primary disease or outgrowth of metastases. Type 1 CD4? T cells facilitate tissue destruction and tumor rejection by providing help to cytotoxic CD8? T cells, while type 2 CD4? T cells facilitate antibody by B cells and polarize immunity away from a beneficial cell-mediated antitumor response [8]. Same observations indicate that T-cell homing to tumor sites does indeed occur, at least in a subset of individual patients. T-cell infiltrates in tumor sites have been observed in patients with melanoma [9, 10], colon cancer [11], ovarian cancer [12], and head and neck cancer [13], among others, and these studies indicate that such infiltrates confer positive prognostic value. In fact, tumor-infiltrating lymphocytes (TILs) are the starting point for the adoptive T-cell therapies recently explored by Rosemberg et al. [14], which have shown preliminary therapeutic success. Human tumors express a number of tumor-associated antigens (TAAs) that represent potential targets for T-cell
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immune responses. However, naı¨ve T cells are incapable of recognizing TAA and need the help of antigen-presenting cells such as dendritic cells (DC) to initiate a fully competent tumor-specific T-cell response. TAAs are overexpressed on cancer cells, whereas they are present in fewer numbers or not expressed on normal cells. Furthermore, therapies specifically targeting TAAs have become very popular in cancer therapy as they cause fewer side effects than traditional cancer regimens [15, 16]. With regard to B cells, more recent experiments indicate that activated B cells and their soluble products, presumably antibodies, can all also facilitate carcinogenesis. Using a transgenic mouse model in which the human keratin 14 promoter drives expression of early region genes of human papilloma virus 16, B cells were shown to promote a chronic inflammatory microenvironment that recruits innate immune cells and factors to the tumor site, thus establishing a stromal environment that supports the novo carcinogenesis. Thus, humoral immunity can enhance malignant transformation by activating the innate immune system [17, 18]. Natural killer cells The network of immune cells that is involved in preventing tumor initiation and metastasis is complex; although the main focus has been on the biology of dendritic cells and the development of cytotoxic T-lymphocyte-based vaccines, recent attention has also concentrated on the role of innate immunity in immune response to cancer. In this contest, natural killer cells (in humans these are CD56? CD3- lymphocytes) are an important component of innate immunity, able to limit viremia and mediate the spontaneous killing of various tumor cells even before the adaptive immune system is activated [19]. NK cells do not kill by a single mechanism, nor do they contribute to tumor surveillance merely by killing. They eradicate tumors by multiple pathways, including apoptosis and direct tumor lysis [20]. While human peripheral blood NK cells have been characterized in considerable detail [21], the NK-cell subset in secondary lymphoid organs has just recently been identified. This subset contributes to the innate and adaptive immune responses to tumor cells via the production of cytokines which promote proliferation of other cells such as dendritic cells [19, 22]. NK cells express surface receptors that receive signals from the environment, which determine their response to foreign or malignant cells. NK cells respond to these signals by producing effector molecules that can both directly suppress tumor growth and convey important information to the rest of the immune system [23]. However, with the exception of allogenic hematopoietic grafts for treating leukemia [24], the role of NK cells in cancer is poorly understood, particularly during its metastatic phase [25].
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Natural killer T cells Natural killer T cells (NKT), which express both NK and TCR, bridge the innate and adaptive immune systems. They are true T cells with ab T-cell receptors and CD3, but they also may have some receptors characteristic of NK cells, such as NK1.1, and are able to kill in an NK-like fashion [26]. Innate and adaptive immune responses have many interactions that are regulated by the balance of signals initiated by a variety of activation and inhibitory receptors. Among these, the NKG2D (CD314) expression, which is a major activating receptor that is constitutively expressed by all NK cells [20, 27], was identified on TNK cells. Tumor cells may overexpress these stress-inducible NKG2D ligands, and NKG2D signaling has been shown to be involved in lymphocyte-mediated antitumor activity [26]. Regulatory T cells The discovery and characterization of regulatory T cells was a significant contribution to our knowledge on the complex interaction between the immune system and cancer. These cells play an important role during the antitumor immune response also following immunotherapeutic treatments [28–30]. In fact, in cancer immunotherapy, the efficacy of vaccinations is often insufficient to activate the antitumor immune response, because of the immunosuppressive effect induced by inhibitory cells, such as Tregs in the tumor microenvironment [31]. The Treg population is characterized by constitutive expression of CD25 and FoxP3. The latter molecule, a key regulator of immune suppression, is a member of the forkhead family of transcription factors critically involved in the development and function of CD25 regulatory T cells. Furthermore, FoxP3 is expressed not only by Tregs but also by melanoma cells, EBV-transformed B cells, and a wide variety of tumor cells lines. Tregs suppress the activities or function of CD4? , CD8? T cell, NK cells, and NKT cells through sever pathway, such as the secretion of suppressive cytokines, cell-to-cell contacting mechanism, and the modulation of function of antigen-presenting cells (APCs). Several reports have documented the presence of Tregs within human tumor tissue, the frequency of which may negatively correlate with survival [32]. Quantification of FoxP3-positive regulatory T cells predicted disease prognosis and progression. Tregs could be used as a novel marker for identifying late-relapse patients who may benefit from additional therapy after standard adjuvant treatment [1]. Dendritic cells Dendritic cells are bone-marrow-hematopoietic-derived APCs with a unique ability to induce both primary and
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secondary T- and B-cell responses as well as immune tolerance [33–35]. They are 10- to 100-fold more potent at activating naı¨ve and memory T cells than other professional antigen-presenting cells [36]. Two distinct lineages of DCs have been described in humans, DC1 and DC2, according to their ability to induce naı¨ve T-cell differentiation to Th1 and Th2 effectors cells, respectively. Human DCs secrete several cytokines that pose a pivotal role in the polarization of Th-cell responses. In particular, IL-12 is important for the development of Th1, whereas IL-4 and IL-10 favor Th2 responses. This makes them important initiators of primary specific immune responses [37]. They regulate both immunity and tolerance, while other cells (i.e., B cells, T cells, and NK cells) are effectors. DCs have been shown to infiltrate many tumors, but both circulating and tumor-infiltrating DCs from patients with cancer appear to be phenotypically and functionally defective. Human DC precursors circulating in the blood initially can express CD2, CD4, CD13, CD16, CD32, and CD33. In contrast, up-regulation of the expression of MHC class II and the absence of lineage markers (markers that are specific for other cell types) including CD14 (monocyte), CD3 (T cell), CD19, CD20, CD24 (B cell), CD56 (natural killer cell), and CD66b (granulocytes) become a hallmark of fully mature DC. Because of their antigen-presenting functions, DCs also express various adhesion and costimulatory molecules like CD11a (LFA-1), CD11c, CD50 (ICAM-2), CD54 (ICAM-1), CD58 (LFA-3), CD102 (ICAM-3), and CD123 (IL-3R a) [38]. The CD11c-negative DCs (expressing high levels of CD123) are designated as lymphoid-derived DC (DC2), whereas the CD11c?/ CD123- cells do identify the myeloid-derived DCs (DC1). Furthermore, DC subsets can be recently identified with specific markers: BDCA1 (CD11c? high/CD123? low myeloid DC); BDCA2 (CD11c-/CD123? high, lymphoid DC); BDCA3 (CD11c? low/CD123-, myeloid CD) [39]. Through their potential capacity to activate tumorspecific T-cell responses, DCs play an important role in cancer immunosurveillance. However, it is known that DCs in many tumors are functionally compromised. This indicates that, besides the direct suppression of T cells by the tumor or the tumor milieu, the suppression of DC differentiation represents an additional important immune escape mechanism [40, 41]. All of these characteristics make these cells unique cancer vaccine adjuvant candidates since they have the essential features for initiating immunity [38]. DCs in cancer immunotherapy are used as vaccine adjuvant to induce specific immunity against tumor epitopes. In general, these therapies aim at breaking the body’s tolerance of the tumor in order to fight it, control it, and even perhaps eradicate it. Finally, DCs are now known to be potent stimulators of NK-cell activation through the action of several cytokines. Human DCs were consistently found
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to stimulate cytotoxicity and IFN-c secretion by NK cells from peripheral blood stimulated with IL-12 [19].
Clin Exp Med (2011) 11:199–210 Table 1 Complications related to T-cell depletion in patients undergoing cytotoxic antineoplastic therapy Infectious
Lymphocyte depletion and recovery following antineoplastic therapy Very complex interactions occur between tumors and the immune system. The immune system plays an important role in the control of the tumor growth, and its direct antitumor activity seems to have a critical impact on the prognosis of the patients with cancer. It has been reported that cellmediated immunity to tumor-associated antigen may predict survival better than tumor stage, grade, and lymph node status [42]. Even if it is clear that patients with cancer display varying degrees of immunosuppression at the time of presentation, prior to initiation of antineoplastic therapy [43], however, CT is considered to be a major cause of immune deficiency in patients with cancer. The immunosuppressive effects of antineoplastic agents such as alkylating agents, fludarabine, melphalan, thiotepa, and cyclophosphamide are well established. Little information is available concerning the actual impact of the immune system of other widely used antineoplastic drugs, such as platinum derivatives, anthracyclines, etoposide, and 5-fluorouracil [44]. The clinical management of patients with cytotoxic antineoplastic therapy involves the maintenance of a high index of suspicion for opportunistic pathogens. The most common infectious complications associated with cytotoxic antineoplastic therapy are bacterial infections that occur in the setting of neutropenia. Clearly, however, patients with cancer are also predisposed to a variety of other infections with viral, fungal, and parasitic pathogens. Furthermore, it is evident that deficiencies in T-cell immunocompetence in patients with cancer contribute to susceptibility to infection with an array of pathogens as well as the development of other complications that are listed in Table 1 [43]. The mechanism by which classical cytotoxic agents induce T-cell depletion has not been well defined, but the effects are quite rapid. With regard to other lymphocyte populations, B cells also sustain profound depletion in the context of dose-intensive multiagent chemotherapy. NK cells, in contrast, appear to be relatively resistant to cytotoxic antineoplastic therapy, raising the possibility that they serve as an important second line of host defense against viral pathogens in this setting [45]. Finally, recent studies have suggested that monocyte populations may contribute to T-cell immunosuppression by the production of suppressive factors that inhibit T-cell function [46, 47]. Dose-dense CT regiments have shown very promising results in the adjuvant treatment of primary breast cancer [48] with less toxicity compared to dose-escalation regimens. Hematological support with granulocyte-colony-
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Viral: Human herpes viruses (herpes simplex types 1& 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus) measles, respiratory syncytial virus, influenza, adenovirus Bacterial: Legionella pneumophila, Lysteria monocytogenes, Salmonella typhimurium, Mycobacterium tuberculosis, Atypical mycobacterium Parasitic: Pneumocystic carinii, Toxoplasma gondii, Cryptosporidia spp Fungal: Candida spp, Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis Non-infectious Post-transfusion graft-versus-host disease EBV-associated lymphoproliferative disorder* * Typically observed only in the setting of T-cell-depleted, allogenic BMT
stimulating factor (G-CSF), either natural or pegylated, was demonstrated to reduce the duration and severity of CTinduced neutropenia and thus infectious complications and hospitalizations. G-CSF also has an impact on the immune system; it has been shown to influence cytokine production and to modify T- and B-lymphocyte subsets [49–51]. In summary, the impact of cytotoxic CT on the immune system has not as yet been fully elucidated. Mackall reported on the immunosuppressive effects of cytotoxic CT, such as a decrease in total T lymphocytes and the CD4? subset following adjuvant CT and radiotherapy for breast cancer and the slow recovery of CD3/CD4 lymphocytes in patients treated with intensive CT [43]. Significant reductions in the absolute number of CD4 lymphocytes were also reported by Sewell et al. [52] in patients with breast cancer treated with standard CT, and by Sara et al. [53] in patients with solid tumors treated with CT. Schroeder and colleagues [54] reported specific alterations of T-cell population in patients with breast cancer, such as a significant reduction in the absolute T-cell number, but not in the CD4/CD8 ratio and a significant increase in the CD3? T cells. In contrast to such aberrations of peripheral blood lymphocyte (PBL) reported in patients submitted to cytotoxic CT, Melichar et al. [55] observed only a few distinct PBL changes in a population of patients with breast cancer and suggested the presence of T-cell activation. Our group previously found little impact of a topotecan-based CT on lymphocyte subsets of either naı¨ve or pretreated patients with ovarian cancer [56]. Afterward, in a recent study, Collova` et al. have suggested that the pegfilgrastimsupported dose-dense adjuvant anthracycline- and taxanebased CT does not significantly affect the immune system of patients with breast cancer. In particular, T-lymphocyte subsets did not show significant changes, except for a
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decrease in the number of T helper (CD4?) cells. Following the discontinuation of CT, the mean values of leukocytes, total lymphocytes, and NK subsets tended to return to baseline values. The substantial preservation of NK and DC during cytotoxic therapy and follow-up probably indicated a preservation of the immunocompetence by these regimens of adjuvant CT. Only B (CD19? , CD20?) and early B (CD20?/CD38?) lymphocytes decreased significantly over the entire CT period, and the decrease persisted at follow-up [44]. Taxanes have been previously reported to exert immunostimulatory effects, which were hypothesized to be implicated in antitumor immune activity [57]. Furthermore, experimental observation suggests that the immune system can play a key role in containing renal cell carcinoma (RCC) in situ [58]; unfortunately, however, in the long term, the immune response against RCC fails to control the disease, which inevitably progresses toward invasive forms. Further evidence of the immune system involvement in RCC control comes from the frequent finding of major T-cell infiltration in the tumor; the presence of clones of antigen-specific T cells in both the primary lesion and draining lymph nodes has been unquestionably demonstrated, and the clone appeared to be able to lyse RCC in vitro [59–61]. Schwaab et al. [62] demonstrated defective antigen presentation by dendritic cells, partly related to the down-regulation of co-stimulatory molecules, such as B7.2, and a consequently decreased recruiting of CD8? cytotoxic lymphocytes infiltrating the tumor. Also, experimental research demonstrated that RCC production of soluble immunosuppression mediators can suppress T-cell response through different mechanism, such as induction of T-cell apoptosis [63], decrease in IL-2 production by CD4 helper T cell, inhibition of the activity of Jak-3 kinase involved in transduction of the signal from IL-2 receptor activation [64], and decreased activation of the nuclear factor NF-kB in the lymphocytes affecting the immune response, resulting in increased susceptibility to apoptosis [65]. Several complex immune defects in patients with RCC, almost solely at the level of cell-mediated immune function, were demonstrated; such dysfunctions are already present at diagnosis and, therefore, not necessarily consequent to disseminated disease. About NK subset, while a statistically significant increase was found in CD56? NK cells relative to controls, the defect in CD16? NK cells appears to be equally important. Indeed, if CD56? NK cells are involved in mechanisms of indirect cytotoxicity [66], only NK cells characterized by the CD16 phenotype can mediate antibody-dependent toxicity [67]. Interestingly, in our recent study, no defect in mature NK cells could be found in our patients; it is however worth reminding that NK cells are more involved in seeking and destroying non-self cells in the general circulation rather than in development cancer sites. We also demonstrated a
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statistically significant increase in T-cell-co-expressing CD4 and CD8 antigens in patients with RCC relative to healthy controls. Finally, though the DC1-to-DC2 subset ratio in circulating dendritic cells appears to be preserved, thus assuring a preferential Th1 response, we found a significant decrease in our patient with RCC in circulating DC [68]. The observation of reduced numbers of NK and DC in the systemic circulation made us wonder whether these cells could be recruited—and thus sequestered—by the tumor. When absolute lymphocyte counts are monitored following cessation of cytotoxic antineoplastic therapy, recovery to baseline values is generally observed within 3 months. With regard to lymphocyte subsets, NK cells frequently reach normal values immediately following cessation of therapy [69]. These are followed by the total B-cell population, whose numbers generally normalize within 1 to 3 months [70, 71], often exhibiting an overshoot such that supranormal values may be observed for a prolonged period following completion of cytotoxic chemotherapy. Restoration of total numbers of peripheral blood CD8 T cells generally occurs within three to 6 months following completion of cytotoxic antineoplastic therapy, with supranormal values for this subset also frequently observed during the initial phase of regeneration [69]. Such normalization of total lymphocyte counts belies the fact that recipients of cytotoxic antineoplastic therapy frequently experience a prolonged CD4 lymphopenia. The degree of CD4? depletion induced by cytotoxic CT occurs in an age-independent fashion and is related to the intensity of therapy. Importantly, however, the recovery of CD4? T-cell population is highly age-related, at least when evaluating children and young adults. The adults generally show a slow, variable rise in CD4? population which predominantly display the memory (CD45RO?) CD4? phenotype over the first year following cessation of CT. During subsequent years, it is not uncommon to see gradual rises in naı¨ve (CD45RA?) CD4? cells in adults as well, although obvious evidence of thymic enlargement is generally not observed. With regard to CD8? T cells, the story is complicated by the existence of multiple CD8? T-cell subsets, many of which recover in an age-independent fashion following cessation of cytotoxic chemotherapy. Within 3 months after cessation of cytotoxic chemotherapy, total CD8? numbers generally return to baseline regardless of patient age. Careful analysis of these populations, however, shows that the bulk of CD8? cells contained within the recovered populations are atypical and represent expansion of a normally minor subset of CD8? T cells which lack the CD28 co-receptor. Indeed, recovery of the CD8? CD28? subset generally does not occur until approximately one year following cessation of therapy [43].
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Cross-link between target therapy and the immune system The role of the dendritic cells on angiogenesis in human tumor Recent studies have shown that the immune system not only is involved in tumor development but also contributes to tumor progression [72, 73]. Stromal and inflammatory cells, including T lymphocytes, mast cells, neutrophils, monocytes, and hematopoietic precursors, might contribute to the modulation of angiogenesis or vasculogenesis by the production of pro- and antiangiogenic mediators and/or by their transdifferentiation into endothelial-like cells. Also, dendritic cells have been shown to regulate angiogenesis in cancer. They have a pivotal role in the onset and regulation of adaptive immune responses. Immature DCs (iDCs) might induce regulatory T cells, thus promoting tolerance, whereas mature DCs stimulate effector T cells, supporting immunity. Therefore, although the primary biological function of DCs is the initiation of specific immune responses, DCs have the ability to regulate inflammatory responses through the release of cytokines and chemokines; they also kill bacteria and regulate angiogenesis, a characteristic that they share with other phagocytes. Our findings indicated that, in colorectal cancer (mCRC), the loss of circulating DCs correlates with tumor burden (suggesting a possible correlation with a more aggressive course of the disease) and with the degree of DC impairment and response to treatment. Our data confirmed that in patients with cancer, at diagnosis, circulating DCs displayed an ‘immature’ phenotype with very low levels of accessory signals for T-cell activation such as CD40 and CD86 and of surface MCHII molecules and with a reduced T-cell stimulation capability [74]. DC express a wide array of pro- and antiangiogenic mediators (Table 2) that might have a significant role in those physiopathological settings characterized by DC activation and angiogenesis, including inflammation, wound healing, atherosclerosis, and tumor growth. Activated DCs exert a potent pro-angiogenic activity that is mediated by the prototypic angiogenic growth factor VEGF-A. In turn, pro- and antiangiogenic mediators can affect the biology of DCs, modulating their differentiation and maturation. Therefore, DCs might exert an important impact on the neovascularization process under different physiopathological conditions, and they can transdifferentiate into endothelial-like cells, possibly contributing to vasculogenesis in the adult as it has been elegantly shown by Sozzani et al. [72] in their recent review (Fig. 1). Recent observations have shown that a tumor microenvironment characterized by the presence of cytokines and lactate will induce the differentiation of monocytes into
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tumor-associated DCs that, in the presence of pro-angiogenic mediators, will transdifferentiate into endothelial-like cells [75]. Similarly, immature DCs transdifferentiate into endothelial-like cells when grown in the presence of a cocktail of pro-angiogenic mediators, including VEGF-A [76]. Taken together, DC might contribute to new vessel formation by two distinct, but possibly cooperative, mechanisms by stimulating angiogenesis from existing vessels through the release of pro-angiogenic factors, and by contributing to vasculogenesis by transdifferentiation into endothelial-like cells. In both cases, VEGF-A appears to have a pivotal role, acting as a direct angiogenic growth factor produced by DCs and inhibiting the functional maturation of DCs, skewing their differentiation into endothelial-like cells [72]. The impact of antiangiogenic therapy on lymphocyte subsets and dendritic cells The increasing amount of knowledge about biological targets is nowadays going to switch the balancing and equilibrium between the medicine for the ‘‘entire population’’ and the medicine for ‘‘the individual’’, in favor of the latter, in order to better aim to a modern concept of ‘‘ideal medicine’’ [77]. In 1971, Judah Folkman was the first to hypothesize the potential therapeutic benefit of targeting tumor angiogenesis [78]. The ultimate goal in antiangiogenic cancer therapies is to starve the tumor by inhibiting tumor vessel growth, thereby blocking the supply of nutrients and oxygen [79]. The VEGF family of proteins is key regulator of normal and tumor angiogenesis and so provides attractive targets for anticancer therapies. The development of antiangiogenic therapies was hypothesized to avoid tumor resistance pathways of traditional anticancer drugs by targeting the vasculature as opposed to the genetically instable and highly mutagenic tumor cell population. The preclinical success of targeting the VEGF pathway using monoclonal antibody (mAb)based therapy further bolstered this hypothesis. In addition, antiangiogenic therapies counteract the inherent disorganization and the abnormalities of the tumor vasculature; this process has been termed ‘‘normalization’’ [80]. Strategies that inhibit the VEGF pathway have proven to be effective in the treatment of solid tumors. Bevacizumab (Avastin Genentech, Inc), a humanized monoclonal antibody, is actually the most specific mAb, targeting the VEGF pathway; it suppresses tumor angiogenesis by direct inhibition of circulating VEGF, preventing the activation of VEGF–VEGFR downstream signal. By contrast, Sunitinib (Sutent, Pfizer) and Sorafenib (Nexavar, Bayer) are multikinase inhibitors that block the tyrosine kinase activity of
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Table 2 Production of pro-angiogenic mediators and antiangiogenic mediators by DCs DC subset
Stimulus
VEGF
Conventional
LPS and PGE2; LPS and calcitriol; CD40L and calcitriol; SAC and calcitriol
FGF2
Conventional
LPS and PGE2
TNF-a
Conventional
LPS, B. henselae; SAC
Pro-angiogenic mediators
Plasmocytoid
HIV
Langerhans
CD40L; tumor microenvironment
IL-6
Conventional
LPS; B. henselae
TGF-b
Langerhans
Tumor microenvironment
CXCL8
Conventional
LPS; CD40L; SAC; B. henselae; influenza virus; bacteria flagellin
Plasmocytoid
Influenza virus, CD40L; CpG
Langerhans Conventional
CD40L Constitutive TNF-a
CXCL5 CXCL1, 2, 3
Conventional
Bacterial flagellin
CCL2
Conventional
Influenza virus; LPS; CD40L; Bacterial flagellin
GM-CSF
Langerhans
Tumor microenvironment
ET-1
Conventional
TNF-a; SAC
OPN
Conventional
IL-10
IL-12
Conventional
PMA and ionomycin; CD40L; SAC; LPS
IL-18
Conventional
Constitutive
Antiangiogenic mediators
Langerhans
Constitutive
IL-10
Conventional
PMA and ionomycin; CD40L; LPS; CpG; B. henselae
TSP-1
Conventional
Constitutive; LPS; SAC; CD40L; TGF-b; PGE2; ATP
PTX3
Conventional
LPS; LPS and IFN-a or-b; LPS and IL-10; LPS and CD40L; IL-1 b; IL-1 b and IL-10; various microbial stimuli
IFN-a/b
Plasmocytoid
CpG; IFN-c; viral infection; HIV-1
CXCL9
Conventional
Bacterial flagellin and IFN-b; LPS and IFN-b; HIV-1; Tat; influenza virus
CXCL10
Conventional
LPS; HIV-1 Tat; influenza virus
CXCL13
Conventional
B. henselae
CCL21
Conventional
Influenza virus
B. henselae, Bartonella henselae; SAC, Staphylococcus aureus Cowan; PMA, phorbol 1-2-myristate 13-acetate
VEGF receptors on endothelial cells, as well as various other kinases that might direct activity. The clinical efficacy of bevacizumab, as a single agent or in combination with other chemotherapies, has been evaluated in many clinical trials, with different levels of efficacy in various types of tumors (non-small cell lung cancer, colorectal cancer, breast cancer, renal cell cancer). Despite an increase in tumor response, only incremental gains in progression-free survival and overall survival have been obtained in most tumors [79, 81–84]. Orally administered small molecular receptors and tyrosine kinase inhibitors, sorafenib and sunitinib have also been approved for metastatic renal cell cancer. Sorafenib is also approved as monotherapy for hepatocellular cancer [85], while sunitinib is approved also for gastrointestinal stromal tumors [86].
VEGF has a central role in promoting and sustaining the tolerance of the immune system to solid tumor outgrowth by negatively influencing on lymphocyte subsets, particularly DCs [72, 87, 88]. Specifically, VEGF binds to hematopoietic progenitor CD34? cells through the VEGF receptor 1 (VEGFR1/Flt-1) and inhibits the activation of the transcription factor NF-kB. A component of NF-kB, RelB, has been implicated in the generation of mature DC [89–94]. The involvement of VEGF in tumor-induced defects in DC differentiation was demonstrated initially in vitro [95] and subsequently in vivo in mice [91, 96]. In recent years, clinical data have supported the important role of VEGF in DC defects also in human cancer. The expression of VEGF negatively correlates with DC numbers in the tumor tissue and peripheral blood of patients with different types of cancer [87, 97–100]. All these data
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Fig. 1 Dendritic cell and circulating endothelial (DC-EC) cell crosstalk. The figure drawn with permission from Sozzani et al. [72] elegantly illustrates the theory (a) that dendritic cells modulate neovascularization by acting on existing vessels through the release of pro- and antiangiogenic factors. Also, the authors propose that DCs contribute to vasculogenesis by transdifferentiation into endothelial-like cells. In turn, pro- and antiangiogenic mediators and cytokines of EC origin, as well as direct EC-DC contact, might affect DC functions and differentiation. b Immature DC (iDCs) activated by pro-inflammatory mediators (LPS or TNF-a) mature to classically activated DC (C-DC) that express high levels of the antiangiogenic IL-12 and PTX3 and very limited amounts of TSP-1. By contrast, highly angiogenic, alternatively activated DC (A1-DC) matured in the presence of the anti-inflammatory molecules calcitriol or PGE2 secrete high amounts of VEGF-A and very limited levels of PTX3. Together with the suppression of IL-12 expression, these features confer very potent angiogenic activity to A1-DC, despite the high levels of TSP-1 production. By contrast, alternative activation of DC, by antiangiogenic IL-10, causes only a very limited up-regulation of VEGF-a and TSP expression, paralleled by potent production of PTX3, thus conferring to A2-DC a limited angiogenic potential
provided a strong rationale for using VEGF signaling inhibitors as a means to improve DC differentiation and immune function in patients with cancer. A phase I trial
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was conducted with VEGF trap (a specific antagonist that binds and inactivates circulating VEGF) in 15 patients with various advanced tumors resistant to conventional treatment. VEGF trap did not affect the total DC population or subsets but significantly increased the proportion of mature DC; however, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens [101]. Osada et al. [102] evaluated the effect of bevacizumab on cancer patients with advanced disease (lung, breast, and colorectal carcinoma). Bevacizumab administration was associated with a decrease in the accumulation of immature DC and a modest increase in the DC population able to recall antigens. The proved clinical efficacy of bevacizumab in metastatic colorectal cancer (mCRC) could be related not only to its well-established effect on tumor neoangiogenesis but also to a counteraction of VEGF-mediated dendritic cell abnormalities. In order to understand more fully the immunological mechanisms of action of bevacizumab, we have focused on its in vivo impact on both the peripheral blood lymphocyte and dendritic cell immunophenotype in patients with mCRC. We performed a prospective multicentric biological– clinical trial in a selected patient population affected by metastatic colorectal cancer and suitable for first-line treatment containing bevacizumab to evaluate the influence of bevacizumab on the immune system and its correlation with clinical outcome [103]. Our mCRC population, despite a normal median leukocyte absolute number, showed a basal impairment of both B- and T-cell compartments, with a deficiency in NK cells. The B-cell deficiency was observed at all steps of differentiation; on the other hand, a more pronounced impairment was evidenced in mature/ commissioned T cells than in immature ones. These in vivo effects are in part in line with the modifications of lymphocyte subsets described in the murine model treated with VEGF continuous infusion [96]. In fact, no expansion of B lymphocytes in patients with mCRC was observed, but impairment of the mature T-lymphocyte subpopulations could be related to the described thymic atrophy in mice due to the blockage of development or migration of bone marrow progenitors into the thymus [104]. Curiously, patient DC profiles at baseline were similar to those of healthy subjects, suggesting that in our population, no critical impairment in immune surveillance against the tumor was evidenced, unlike previous experience [105, 106], even in patients with colorectal cancer [74]. The anti-VEGF therapy was able to revert the basal impairment of the majority of lymphocyte subsets, and it also showed a positive effect on mature T cells and T helper cells (related to the response to treatment) and on B lymphocytes (related to progression-free survival) [103].
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Conclusions Cytotoxic chemotherapy is the primary contributor to the clinical immunodeficiency that can be observed during and after the treatment course. This problem is frequent and severe in patients with hematological malignancies and especially following allogenic bone marrow transplantation where the combination of underlying disease, intensity of the preparative regimen, T cell depletion of the marrow graft, post-transplant graft-versus-host disease (GVHD) prophylaxis, and the immune suppressive effects of GVHD itself contribute to a high incidence of opportunistic complications. Patients affected by solid tumors generally show variable levels of immunosuppression at the diagnosis and, in most cases, following the initiation of chemotherapy, opportunistic infections and other complications due to T-cell immunodeficiency may occur, but they are often transitional and, anyway, do not critically compromise the patient. In recent years, considerable attention has been paid to the combination of antiangiogenic therapy with conventional antineoplastic drugs for the treatment of patients with solid tumors in advanced stage. In this field, the concepts of linking antiangiogenic therapy with modulation of the immune system and antitumor efficacy have yielded interesting results. Our recent experience in the study of lymphocyte subpopulations and dendritic cell phenotyping in patients with advanced cancer (before and during treatment) indicates that, with respect to other approaches (i.e., high-dose or dose-dense chemotherapy), this combination therapy does not negatively influence patient immunoresponse. On the contrary, it seems to be able to totally ameliorate the T-cell compartment (probably also enhancing the antigenpresenting function of dendritic cells) with a positive effect on clinical response, as well as to exert a positive effect on B lymphocytes that can translate into a longer progressionfree survival of the patients. In a clinical perspective, this favorable immunological effect can be relevant and deserves further studies specifically designed to combine antiangiogenic-based protocols with active immunotherapy in solid tumors. Acknowledgments The present work was partly supported by a Research grant (scientific project n. 08010901/09 to M. Danova) from the ‘‘Fondazione IRCCS Policlinico S. Matteo’’, Pavia. Conflict of interest
None.
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