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Free delivery worldwide. A number of clinical observations have also supported the evidence for intrinsic immunosurveillance of tumors. An important role of T cells in preventing recurrent leukemia following allogeneic bone marrow transplantation was also reported 25 , Other observations have been less profound; nonetheless, a low natural killer NK cell activity has been reported in patients with breast cancer that had a family history of this tumor and in their first-degree relatives that were clinically asymptomatic Recent clinical studies also supported the existence of an antitumoral immune response in cancer patients 28—30 and an important role of cytotoxic T cells CTLs and NK cells in this process 30 , These findings are complemented by the development of cancer vaccines and studies of new combination of these with immunological inhibitory checkpoints 17— This combination of data has resulted in a contemporary view of cancer as a disorder of cell growth, survival and movement, with a major facilitator of that progression being disruption and dysregulation of the immune response In trying to characterize the immune response to tumors, it must be understood that both innate and adaptive immunities participate in the control of tumor cell death and survival.
Innate response typically used germ line-encoded receptors to respond to highly conserved structural motif found on pathogens, whereas adaptive responses rely on specialized undergoing specific somatic mutations to generate highly specific, high-affinity immunologic receptors such as T-cell receptors and immunoglobulins that can be highly specific to pathogens and generate immunologic memory. Highly specialized and professional antigen-presenting cells, termed dendritic cells DCs , play a central role in activation of the adaptive immune response and the highly efficient eradication of tumor cells.
DCs do this by taking up foreign antigens, becoming activated by appropriate costimulation and migrating to lymphoid organs to present their antigenic payload to adaptive immune cells 33— Although the recognized immunomodulatory elements can modify this adaptive response to the tumor, additional methods of immune escape can occur due to specific behavior of the tumor cells. For example, an effective antigen-specific immune response may lead to epigenetic changes within the tumor that can result in loss of expression of tumor antigens.
In addition, the malignant cells are advantage if they can create a microenvironment that creates poor conditions to stimulate T cells or poor conditions for the function of tumor-specific cytotoxic T cells The molecular mechanisms of evading host immunity have become increasingly clear and include a variety of strategies such as i loss of antigen processing and presentation via downregulation of surface molecule expression e.
Among the tumor-released soluble factors and cytokines that can augment the normal immune response are tumor necrosis factor-alpha 44 , small molecules of prostaglandin E2, histamine and epinephrine Moreover, tumor microenvironments that favor chronic inflammation enable a population of tumor cells to escape from antitumor immunity, thus supporting carcinogenic progression 33 , 59 , Recent transplantation experiments showed that cancer cells that had originated in immunodeficient animals were often unable to initiate secondary tumors in syngeneic immunocompetent hosts.
In contrast, cancer cells from tumors that originated in immunocompetent animals could initiate tumors when adoptively transferred in both immunocompetent and immunodeficient mice 61 , This means that when highly immunogenic cancer cells are eliminated by immunocompetent hosts, weakly immunogenic cancer cells can escape host immunity with a capacity to form tumors in both immunodeficient and immunocompetent hosts, thus conferring immunological protection of the tumor cells from immunological detection and destruction 2 , Another broader process, i.
The objective of this review is to discuss possible pathways that could be involved in the modulation of immunosurveillance rather than to provide a full toxicological evaluation of the chemicals. Immunotoxicity can be defined as any modulation activation, suppression or deviation of immune responses by chemicals that cannot be related to the infection with a certain type of the pathogen For some chemicals, significant immune effects occur at doses that are below those where acute cellular toxicity is observed — Most of in vivo immunological experiments are usually performed on healthy adult animals.
However, immunotoxic effects may change when the immune system is compromised due to existing disease or when immune system is not yet fully developed i. This would permit greater likelihood of tumor cells escaping host immunity and establishing a malignant condition. A number of chemicals with immunotoxic potential have been identified in previous studies and shown to increase the risk of cancer for exposed individuals. For example, perfluorinated compounds, polychlorinated biphenyls and organochlorine pesticides might increase cancer risk, especially among individuals that have genetic polymorphisms associated with metabolism of those compounds — Others have shown that maternal and perinatal exposures to pesticides were associated with increased risk of lymphoma later in life , Factors other than exposures to chemicals from anthropogenic environment can potentially interfere with the relationships between chemical compounds and the host immune response and might thus modify the risk of tumor development and progression.
An example of such a modifying factor is the immune status of the organism at the time of chemical exposure. Animal studies showed that an immunocompromised status was associated with a higher risk of spontaneous and chemically induced tumors 60 , — And chemically induced immunosuppression might impact the ability of an animal to reject cancer cells, depending on the severity of immunosuppression and the type of defect e. However, information on the role of coexisting immunosuppression, relative susceptibility to chemical exposures and their effects on malignant risk are sparse for human.
Clinical observations of human immunodeficiency virus-infected patients and organ transplant recipients that had displayed increased risk of malignant development or transformation are consistent with the role of immunosurveillance in carcinogenesis — These observations led to the hypothesis that immunodeficient or immunosuppressed individuals might have a higher risk of tumor development when exposed to chemicals that affect immune responsiveness compared with immunocompetent individuals.
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On an individual level, many disparate factors influence the capacity of any particular compound to affect host immunity. These include genetic variability in the capacity to metabolize chemicals, coexisting immunosuppressive conditions e. But if a sufficiently large population i. Chemical compounds can affect the immune response through different pathways. For example, certain endocrine-disrupting chemicals can increase breast cancer risk through genes that are involved in estrogen-dependent induction of immune evasion, including estrogen receptor-mediated genes EGR3 Polycyclic aromatic hydrocarbons inhibit differentiation and maturation of DCs Moreover, phytoestrogens, phthalates, bisphenol A, parabens and various pesticides, herbicides and fungicides accumulate in human tissues and in wildlife, thus increasing the time of exposure.
For example, atrazine, which is a widely used broad-spectrum chloro-s-triazine herbicide, impacts the maturation of DCs , and decreases expression levels of major histocompatibility complex class I Moreover, atrazine persists in the soil and surface water for several months — and its effects on the immune system can persist long after initial exposure , In addition to the complicating impact of bioaccumulation, the non-monotonic dose response to these chemicals makes evaluation of the health impacts of such chemicals even more challenging Since the effects seen at high doses of exposure cannot be used for extrapolations into the low-dose range, direct low-dose testing is required to evaluate the effects.
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In the risk assessment procedure, the low-dose effects are observed at the doses near the lower end of the dose—response curve. The low-dose estimates for each chemical are based on various parameters of dose—response analysis, including the reference dose, which is an estimate with uncertainty that can span an order of magnitude of a daily oral exposure to the human population, including susceptible populations, which is likely to be without an appreciable risk of deleterious effects during a lifetime. The reference dose is generally derived from the no observed adverse effect level or lowest observed adverse effect level.
Both the no observed adverse effect level and lowest observed adverse effect level are two commonly used toxicological endpoints presented in Table 4. Generally, the reference dose is used in the U. Additionally, the no observed adverse effect level is a concentration of a chemical or compound that is associated with no observed adverse effects in tested organisms, and the lowest observed adverse effect level is a concentration of a chemical or compound that is associated with the lowest observed level of adverse effects in test organisms.
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Another factor that makes chemical exposure studies in carcinogenesis challenging is the latency period. For example, the shortest latency is often observed in the settings of pancreatic and cervical cancer, and the longest latency is seen in the settings of prostate and grade I breast cancer , Moreover, when multiple chemical compounds act synergistically, the effects can occur at much lower doses compared with the dose at which a single chemical exposure might exert a detectable health effect in human subjects.
The National Report on Human Exposure to Environmental Chemicals — provides some information on population heterogeneity by the level of bioaccumulation and excretion of various compounds Other examples are pesticide metabolites including 2,4- and 2,5-dichlorophenols, phytoestrogens e.
Additional examples include ethyl paraben an antifungal preservative also known as food additive E and n -propyl paraben used as a preservative in water-based cosmetics and as food additive E , metabolites of pesticides [e. Finally, 1-hydroxynaphthalene 1-naphthol , which is a metabolite of carbaryl, is used in plasticizers, dyes, synthetic leather tanning chemicals and in moth repellents.
It also displays heterogeneity in bioaccumulation and excretion studies in the U. Note that compared with currently unrecognized human carcinogenic chemicals, bioaccumulation and excretion of compounds that are already recognized as human carcinogens appear to be less heterogeneous in the U. This allows one to hypothesize that known carcinogenic compounds may have more unified bioaccumulation and excretion patterns in the population, which also assists in recognizing them already as carcinogens. The U.
Deposition of anthropogenic compounds on monuments and their effect on airborne microorganisms
One important focus of ToxCast is the measurement of chemically induced perturbation of critical cellular signaling pathways that may represent potential modes of chemical toxicity These genes are associated with effective immune response in both animals and humans When multiple chemicals impact antitumor immune responses, the resultant cumulative effects of these exposures may impart a greater relative risk of carcinogenesis and tumor development, particularly in the context of multiple exposures affecting the same genetic targets The EPA-screened chemicals included in Table 1 carried the highest scores for the ToxCast immune system disruption counts with the respective number of activated associated genes.
The potency of an assayed chemical that gave a positive i. Note that the use of nominal potency in determining hazard identification has been challenged because in vitro assays cannot account for in vivo impacts of a compounds bioavailability, metabolic clearance and exposure The in vitro to in vivo extrapolation using information on human dosimetry and exposure is valuable in assessing the validity of high-throughput in vitro screening to provide hazard predictions at the level of the organism , We referred to the ToxCast database to determine which chemicals aligned with immune system evasion mechanisms that were relevant in carcinogenesis.
Since chronic inflammation and immune responsiveness in carcinogenesis are both linked to, and initiated at the premalignant stages of tumor development , , it is understandable that ToxCast data sets describe pathways that are related to both inflammation and immune evasion as putative immune disruption mechanisms , We selected the pathways that were related specifically to immune evasion as a cancer hallmark by comparative analysis of existing studies in the settings of both inflammation and immunosurveillance with the results on immune disruption presented by ToxCast.
Specifically, ADORA1 was involved in the immune response to thyroid cancer by encoding adenosine receptors that inhibited T-cell responses.
Other examples included the participation of CCL2 in immune system evasion by recruiting immune suppressor cells to the tumor microenvironment 67 , and CCL26, which helped to promote a Th2-dominant tumor microenvironment that was beneficial for tumor cells Similarly, others showed that CD69, which is among the earliest cell-surface expressed molecules, was induced during lymphocyte activation 70 , and COL3A1, which might be involved in tumor cell evasion of immune surveillance Moreover, the expression of the EGR1 gene participates in immune evasion mechanisms of infectious agents 73 , although its role in tumor evasion e.
Finally, IL-6 is crucial for both tumor growth and immunosuppression Additional pathways contribute to immune surveillance that is also associated with carcinogenesis and tumor progression. The local immune response of Epstein—Barr virus-associated tumors to infiltrating T cells might be suppressed by enhancing cytokine and cellular growth factors like IGF1 The collection of genes involved suggests several candidate-signaling pathways that are capable of participating in chemically induced immune evasion.
Indeed, some pathways e. However, some pathways e. In addition, signaling pathway cross talk might play a role in affecting host immunity. Candidate-signaling pathways potentially involved in chemically induced tumorigenesis and related to immune evasion hallmark: three chemicals from different groups are selected as examples. There are also intracellular signaling pathways that are critical in regulating DC differentiation, survival and activity, which could be activated or inhibited through signal-mediated cross talk. Additionally, chemicals in the environment affect several candidate immune evasion pathways that are involved in antitumor immunity.
Monoclonal antibodies inhibiting these pathways have demonstrated the effectiveness of anticancer effects in certain types of tumor 77 , Consequently, these pathways represent excellent candidates for further studies of the effects of disruptive or agonistic chemicals of the immune response in human carcinogenesis. Factors other than exposures to chemicals from anthropogenic environment can potentially interfere with the relationship between chemical compounds and host immunity, which might modify the risk of tumor development and progression.
One such factor is the immunological status of the organism at the time of environmental chemical exposure. Animal studies showed that an immunocompromised state was associated with a higher risk of spontaneous and chemically induced tumors 60 , — Chemically induced immunosuppression can impact the ability of an animals to reject cancer cells, and this depends on the extent of immunosuppression and the type of defect e. However, information on the role of coexisting immunosuppression in the human system and their susceptibility to chemical exposures is sparse and is currently insufficient to suggest the role of immunosuppression in chemical carcinogenesis.
Environmental chemicals that impact multiple pathways associated with immune dysfunction may also increase the risk of diseases other than cancer.
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The dysfunction of the immune system caused by some endocrine-disrupting chemicals may lead to lower effectiveness of immune response to infection or to the allergy and autoimmune diseases due to the hyperreactivity of immune response For example, exposures to pesticides, solvents and air pollutants have been shown to be associated with the immune response dysregulation and inflammatory dysfunction and contributed to higher risk of asthma and allergies Specifically, human bronchial epithelial cells treated with butylbenzyl phthalate, bis 2-ethylhexyl phthalate, dibutyl phthalate and diethyl phthalate increased bronchial smooth-muscle cell proliferation and migration, suggesting a role of these chemicals in asthma airway remodeling , There are also increasing evidence from the animal studies that in utero or neonatal exposures to bisphenol A are associated with higher risk of immune system dysregulation and metabolic syndrome that may develop later in life — For addition, certain environmental chemicals may cause the changes in response of immune system to infectious agents, thus increasing risk of adverse outcomes of respiratory infections For example, it has been shown that higher bisphenol A levels were associated with lower levels of anticytomegalovirus antibodies in humans, thus suggesting that exposure to this chemical may attenuate antiviral immunity Based on the number of variables involved in this field and the paucity of data in this area of research, we believe that future research will need to focus on environmentally relevant low-dose exposures to mixtures of chemicals that are known to have a disruptive impact on immune system tumor surveillance and elimination.
Given that the pathways involved in immune evasion might also participate in other hallmarks of cancer, we undertook a mapping exercise to identify cross-hallmark relationships that have been reported for the key mechanisms and the disruptive chemicals that we identified. In particular, this heuristic could be useful for researchers who would like to try to predict potential synergies that might emerge when testing low-dose exposures to mixtures of chemicals for this purpose. Interrelations of the pathways involved in immune evasion and other cancer hallmarks as described in Hanahan et al.
Pathways that have opposing action with a particular hallmark i. When the results were mixed i. Chemicals that were found to have opposing actions in a particular hallmark i. When the effects were mixed i. To conduct this cross-hallmark activity, our team selected nine prototypic chemicals drawn from a list of 20 chemicals as listed in Table 1. The prototypic chemicals chosen were maneb, pyridaben, pyraclostrobin, fluoxastrobin, azamethiophos, triclosan, atrazine, bisphenol A and diethylhexyl phthalate.
Several examples of the interrelations of the pathways involved in immune evasion and other cancer hallmarks are presented in Table 3. For example, chemical exposures that affect chemokine signaling pathways could also deregulate metabolism, the evasion of antigrowth signaling, angiogenesis, resistance to cell death, sustained proliferative signaling, tissue evasion and metastasis, tumor-promoting inflammation and affect the tumor microenvironment. Disruption of the IGF-1 signaling pathway could affect metabolism, evade antigrowth signaling, resistance to cell death, sustained proliferative signaling, tissue evasion, tumor-promoting inflammation and tumor microenvironment hallmarks.
Table 4 shows where there have been reports of cross-hallmark effects by the chemicals that we selected.
For example, maneb displays the widest spectrum of potential effects on multiple pathways among fungicides, i. Two other fungicides pyraclostrobin and fluoxastrobin affected only the hallmarks of genetic instability and tumor-promoting inflammation. Among fungicides, currently only maneb is reported to exhibit limited carcinogenicity in humans as determined by the U.
Maneb was registered in the USA in for use on food including potatoes and tomatoes and ornamental crops to prevent their damage in the field and to protect the harvested crops from deterioration during storage and transportation , Pyraclostrobin and fluoxastrobin the chemical class of strobins have been used since the early s; therefore, there are less data available on these fungicides compared with longer periods of observation for maneb. Pyraclostrobin is a broad-spectrum fungicide that is used in both agricultural cereal grains, fruits and vegetables and non-agricultural settings e.
Pyraclostrobin is one of the most frequently applied fungicides for grapes, apricots, tomatoes, sweet cherries and plums. Fluoxastrobin is used to prevent diseases in crops such as wheat, barley, corn, soybean, potato, tomato, pepper, strawberry and turf plots i.
It is likely that both fluoxastrobin and pyroclostrobin are also endocrine-disrupting fungicides In addition to immune system evasion, atrazine a triazine herbicide that is used primarily in corn production may also interfere with other hallmarks including dysregulated metabolism, genetic instability, sustained proliferative signaling and tumor-promoting inflammation. Atrazine is the most common pesticide contaminant of ground and surface water in the USA , Since , atrazine has been reported as an endocrine disruptor for both androgen- and estrogen-mediated processes , Additionally, two insecticides, pyridaben and azamethiphos, have broader potential effects related to cancer hallmark pathways, in addition to their effects on immunosurveillance, i.
Moreover, exposure to azamethiphos impacts genetic instability. Pyridaben is a pyridazinone derivate that is widely used as an acaricide and insecticide to control mites, white flies and aphids. Azamethiphos is a widely used organophosphate pesticide in the control of cockroaches and flies in buildings and warehouses.