RESUMO
Dysregulation of regulatory T cells (Tregs) is described in the context of inflammatory and autoimmune diseases, and cancer. Forkhead box P3 (FOXP3) is a transcription factor that its activity is an indicator of Treg identity. FOXP3 induces metabolic versatility in intra-tumoral Tregs, so that its deficiency mediates Treg instability or even gives rise to the acquisition of effector T cell phenotype. FOXP3 dysregulation and defectiveness occurs upon ubiquitination, methylation and presumably acetylation. Stimulators of PTEN, mammalian target of rapamycin complex 2 (mTORC2), and nucleus accumbens-associated protein-1 (NAC1), and inhibitors of B lymphocyte-induced maturation protein-1 (Blimp-1), Deltex1 (DTX1) and ubiquitin-specific peptidase 22 (USP22) are suggested to hamper FOXP3 stability, and to promote its downregulation and further Treg depletion. A point is that Treg subsets reveal different reliance on FOXP3, which indicates that not all Tregs are strictly dependent on FOXP3, and presumably Tregs with different origin rely on diverse regulators of FOXP3 stability. The focus of this review is over the current understanding toward FOXP3, its activity in Tregs and influence from different regulators within tumor microenvironment (TME). Implication of FOXP3 targeting in cancer immunotherapy is another focus of this paper.
Assuntos
Imunoterapia , Neoplasias , Humanos , Linfócitos T Reguladores , Regulação da Expressão Gênica , Neoplasias/patologia , Fatores de Transcrição Forkhead/metabolismo , Microambiente TumoralRESUMO
Low frequency of durable responses in patients treated with immune checkpoint inhibitors (ICIs) demands for taking complementary strategies in order to boost immune responses against cancer. Transforming growth factor-ß (TGF-ß) is a multi-tasking cytokine that is frequently expressed in tumours and acts as a critical promoter of tumour hallmarks. TGF-ß promotes an immunosuppressive tumour microenvironment (TME) and defines a bypass mechanism to the ICI therapy. A number of cells within the stroma of tumour are influenced from TGF-ß activity. There is also evidence of a relation between TGF-ß with programmed death-ligand 1 (PD-L1) expression within TME, and it influences the efficacy of anti-programmed death-1 receptor (PD-1) or anti-PD-L1 therapy. Combination of TGF-ß inhibitors with anti-PD(L)1 has come to the promising outcomes, and clinical trials are under way in order to use agents with bifunctional capacity and fusion proteins for bonding TGF-ß traps with anti-PD-L1 antibodies aiming at reinvigorating immune responses and promoting persistent responses against advanced stage cancers, especially tumours with immunologically cold ecosystem.
Assuntos
Neoplasias , Fator de Crescimento Transformador beta , Humanos , Fator de Crescimento Transformador beta/metabolismo , Ecossistema , Neoplasias/tratamento farmacológico , Transdução de Sinais , Fatores de Crescimento Transformadores , Antígeno B7-H1/metabolismo , Microambiente TumoralRESUMO
Strategies for non-invasive biomarker discovery in early detection of cancer are an urgent need. Extracellular vesicles (EVs) have generated increasing attention from the scientific community and are under intensive investigations due to their unique biological profiles and their non-invasive nature. EVs are membrane-enclosed vesicles with variable sizes and function. Such vesicles are actively secreted from multiple cell types and are considered as key vehicles for inter-cellular communications and signalling. The stability and potential to easily cross biological barriers enable EVs for exerting durable effects on target cells. These along with easy access to such vesicles, the consistent secretion from tumour during all stages of tumorigenesis and their content providing a reservoir of molecules as well as mirroring the identity of the cell of origin are virtues that have made EVs appealing to be assessed in liquid biopsy approaches and for using as a promising resource of biomarkers in cancer diagnosis and therapy and monitoring targeted cancer therapy. Early detection of EVs will guide time-scheduled personalised therapy. Surveying reliable and sensitive methods for rapid isolation of EVs from biofluids, the purity of isolated vesicles and their molecular profiling and marker specification for clinical translation in patients with cancer are issues in the area and the hot topics of many recent studies. Here, the focus is over methods for EV isolation and stratification for digging more information about liquid biopsy-based diagnosis. Extending knowledge regarding EV-based strategies is a key to validate independent patient follow-up for cancer diagnosis at early stages and inspecting the efficacy of therapeutics.
Assuntos
Vesículas Extracelulares , Neoplasias , Humanos , Vesículas Extracelulares/metabolismo , Biópsia Líquida/métodos , Neoplasias/diagnóstico , Neoplasias/terapia , Neoplasias/metabolismo , Transporte Biológico , Membranas/metabolismoRESUMO
Evolution of tumor hallmarks is a result of accommodation of tumor cells with their nearby milieu called tumor microenvironment (TME). Accommodation or adaptive responses is highly important for a cell to survive, without which no cell is allowed to take any further steps in tumorigenesis. Metabolism of cancer cells is largely depended on stroma. Composition and plasticity of cells within the stroma is highly affected from inflammatory setting of TME. Hypoxia which is a common event in many solid cancers, is known as one of the key hallmarks of chronic inflammation and the master regulator of metastasis. Transforming growth factor (TGF)-ß is produced in the chronic inflammatory and chronic hypoxic settings, and it is considered as a cardinal factor for induction of all tumor hallmarks. Aging, obesity and smoking are the main predisposing factors of cancer, acting mainly through modulation of TME.
Assuntos
Neoplasias , Transformação Celular Neoplásica , Humanos , Microambiente TumoralRESUMO
Colorectal cancer (CRC), and breast, ovarian, pancreatic and prostate cancers are generally considered as low immune-reactive cancers that represent either limited infiltration of immune cells or extensive infiltration of immunosuppressive T cells. Interaction between programmed death ligand 1 (PD-L1) with programmed death-1 receptor (PD-1) is important for immune evasion. Tumors positive for PD-L1 generally show higher responses to the immune checkpoint inhibition (ICI); however, the high presence of PD-L1 in a tumor is a predictor of poor prognosis. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but responses to the ICI is meaningful. It seems that in a tumor both the PD-L1 expression and TIL infiltration is required for improving responses to the anti-PD-1/PD-L1 immunotherapy. Combination of anti-PD-1/PD-L1 with immune modulatory drugs, such as C-X-C chemokine receptor type 4 (CXCR4), poly (ADP-ribose) polymerase (PARP) or transforming growth factor (TGF)-ß inhibitors has shown meaningful clinical benefits.
Assuntos
Antígeno B7-H1/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Humanos , Fatores Imunológicos/imunologia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T/imunologiaRESUMO
Current research in cancer therapy aims to exploit efficient strategies to have long-lasting effects on tumors and to reduce or even revoke the chance of recurrence. Within the tumor stroma, O2 and nutrients are abnormally distributed between various cells (preferentially for supplying cancer cells), the immune contexture is abnormally positioned (permissive essentially for cells exhibiting tumor-promoting capacity), the fibroblast and fibrotic content is abnormally distributed (presence of both extracellular matrix [ECM] stiffening and ECM-degrading factors both for tumor-promoting purposes), and the tumor vasculature is abnormally orchestrated (for hindering drug delivery and increasing the chance of tumor metastasis). Resistance is actually an adaptive response to an imbalance in the tumor ecosystem; thus, the key consideration for effective cancer therapy is to bring back the normal status in this ecosystem so as to reach the desired durable outcome. Vascular normalization, metabolic modulation (glucose delivery in particular), balancing cellular dispersion, and balancing the pH rate and O2 delivery within the tumor microenvironment are suggested strategies to reverse abnormality within the tumor stroma.
Assuntos
Matriz Extracelular/patologia , Fibroblastos/patologia , Neoplasias/patologia , Microambiente Tumoral , Animais , Matriz Extracelular/imunologia , Fibroblastos/imunologia , Humanos , Neoplasias/imunologiaRESUMO
Tumor cells need to cope with the host environment for survival and keep growing in hard conditions. This suggests that tumors must acquire characteristics more potent than what is seen for normal tissue cells, without which they are condemned to disruption. For example, cancer cells have more potent redox tolerance compared with normal cells, which is due to their high adaptation to an oxidative crisis. In addition, increased demand for bioenergetics and biosynthesis can cause a rise in nutrient uptake in tumors. Utilizing nutrients in low nutrient conditions suggests that tumors are also equipped with adaptive metabolic processes. Switching the metabolic demands toward glucose consumption upon exposure to the hypoxic tumor microenvironment, or changing toward using other sources when there is an overconsumption of glucose in the tumor area are examples of fitness metabolic systems in tumors. In fact, cancer cells in cooperation with their nearby stroma (in a process called metabolic coupling) can reprogram their metabolic systems in their favor. This suggests the high importance of stroma for meeting the metabolic demands of a growing tumor, an example in this context is the metabolic symbiosis between cancer-associated fibroblasts with cancer cells. The point is that redox tolerance and metabolic reprogramming are interrelated, and that, without a doubt, disruption of redox tolerance systems by transient exposure to either oxidative or antioxidative loading, or targeting metabolic rewiring by modulation of tumor glucose availability, controlling tumor/stroma interactions, etc. can be effective from a therapeutic standpoint.
Assuntos
Transformação Celular Neoplásica , Neoplasias , Microambiente Tumoral , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Estresse OxidativoRESUMO
Cold tumors generally show low mutational burden and low infiltration of effector T cells. The pancreas, prostate, ovary, breast, and colon are placed into the category of cold tumors. In such tumors, effector T cells are either excluded from the tumor area or taken away from being in contact with tumor cells. The stromal reaction in the form of desmoplasia is important for the pathogenesis of tumors like the pancreas. Besides acting as a barrier for the penetration of drugs into the tumor area, the dense stroma presumably creates an immunosuppressive tumor microenvironment (TME), which accounts for low responses from tumor to immunotherapy. Cancer stem cells (CSCs) are an important part of the immunosuppressive complex within the TME. The presence of CSCs within the TME is related negatively to the activity of the antitumor immune system. Here, the question is how desmoplastic aggregates can influence the functionality of CSCs for promoting a cold pancreatic tumor immunity? This review is aimed at responding to this question, the disruption of which can be an effective strategy for improving responses from cold tumors to immunotherapy.
Assuntos
Tolerância Imunológica , Células-Tronco Neoplásicas/imunologia , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Humanos , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
Tumors are equipped with a highly complex machinery of interrelated events so as to adapt to hazardous conditions, preserve a growing cell mass and thrive at the site of metastasis. Tumor cells display metastatic propensity toward specific organs where the stromal milieu is appropriate for their further colonization. Effective colonization relies on the plasticity of tumor cells in adapting to the conditions of the new area by reshaping their epigenetic landscape. Breast cancer cells, for instance, are able to adopt brain-like or epithelial/osteoid features in order to pursue effective metastasis into brain and bone, respectively. The aim of this review is to discuss recent insights into organ tropism in tumor metastasis, outlining potential strategies to address this driver of tumor aggressiveness.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias Encefálicas/secundário , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/terapia , Osso e Ossos/patologia , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Movimento Celular/genética , Proliferação de Células/genética , Epigênese Genética , Humanos , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Metástase Linfática/genética , Transdução de Sinais/genética , Microambiente Tumoral/genéticaRESUMO
Solid cancers comprise a large number of new cases and deaths from cancer each year globally. There are a number of strategies for addressing tumors raised from solid organs including surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, combinational therapy, and stem cell and extracellular vesicle (EV) therapy. Surgery, radiotherapy, and chemotherapy are the dominant cures, but are not always effective, in which even in a localized tumor there is a possibility of tumor relapse after surgical resection. Over half of the cancer patients will receive radiotherapy as a part of their therapeutic schedule. Radiotherapy can cause an abscopal response for boosting the activity of the immune system outside the local field of radiation, but it may also cause an unwanted bystander effect, predisposing nonradiated cells into carcinogenesis. In the context of immunotherapy, immune checkpoint inhibition is known as the standard-of-care, but the major concern is in regard with cold cancers that show low responses to such therapy. Stem-cell therapy can be used to send prodrugs toward the tumor area; this strategy, however, has its own predicaments, such as unwanted attraction toward the other sites including healthy tissues and its instability. A substitute to such therapy and quite a novel strategy is to use EVs, by virtue of their stability and potential to cross biological barriers and long-term storage of contents. Combination therapy is the current focus. Despite advances in the field, there are still unmet concerns in the area of effective cancer therapy, raising challenges and opportunities for future investigations.
Assuntos
Neoplasias/terapia , Terapia Combinada , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias/patologia , Neoplasias/cirurgiaRESUMO
Spinal cord injury (SCI) is a common devastating condition that causes neuronal loss and dysfunction. Neuroinflammation takes cardinal roles in the pathogenesis of SCI, and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome is a mediator of inflammatory reactions occurring in SCI patients. The present study was designed to survey possible relation between thoracic segments whereby injury occurs with the activity of NLRP3 inflammasome complex, and to find the influence of hormonal therapy on the outcomes. Adult male Wistar rats underwent contusion SCI model at three different thoracic segments T1, T6 and T12, then receiving subcutaneous injection of either 10 mg/kg melatonin or 25 µg/kg 17-ß estradiol (E2) every 12 hours until 72 hours post-SCI. Inflammasome activity was assessed before and at the end of hormonal therapy. SCI rats showed decreased locomotor activity and myelination, and increased activity of the NLRP3, apoptosis-associated speck-like protein (ASC) and caspase-1 at gene and protein levels. Release of interleukins (ILs) 18 and 1ß was also augmented after SCI (P < 0.0.5). Hormonal therapy was most effective for targeting mRNA activity at T6 segment. Treatment with either melatonin or E2 caused a decrease in the protein activity of NLRP3 inflammasome at all segments (P < 0.0.5), except for T6 that NLRP3 protein had no response to melatonin. IL-1ß showed decreased activity in response to hormonal therapy at all segments, whilst IL-18 protein had no change at T1 segment. It is understood that although no alteration in the activity of NLRP3 was found for SCI at different segments, the response to hormonal therapy was influenced by segment. SIGNIFICANCE OF THE STUDY: From our results, the NLRP3 inflammasome activity is not influenced by segment, but there are differences in the effect of hormonal therapy on inflammasome activity at different segments in response to melatonin or E2. These findings also provide the beneficial effects of melatonin or E2 on inflammation caused by spinal cord injury in different thoracic segments. Finally, these data can have therapeutic importance for hormone therapy of spinal cord injury.
Assuntos
Estradiol/uso terapêutico , Inflamassomos/metabolismo , Melatonina/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/genética , Caspase 1/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Esquema de Medicação , Estradiol/farmacologia , Interleucina-18/análise , Interleucina-18/metabolismo , Interleucina-1beta/análise , Interleucina-1beta/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Melatonina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ratos , Ratos Wistar , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologiaRESUMO
PURPOSE: The present study aimed to explore the associations between the expression pattern of molecules in the Notch pathway in the cumulus cells of polycystic ovary syndrome (PCOS) patients and the quality of zygotes and embryos. METHODS: A total of 200 cumulus complexes surrounding mature oocytes were obtained from 40 patients with and without PCOS undergoing intracytoplasmic sperm injection (ICSI). The expressions of Notch-1, Notch-2, and Notch-3 genes were examined by Reverse Transcription Q-PCR assay. Moreover, immunocytochemistry was performed for the expressions of Jagged-1 and Jagged-2 proteins. The correlations between the Notch receptors and their ligand expressions and the qualities of the zygote and embryo were investigated. RESULTS: The expression levels of Notch-2, Notch-3, Jagged-1, and Jagged-2 were significantly lower in patients with PCOS than in normal women (p < 0.05), while Notch-1 showed no meaningful difference between the groups. A positive correlation was found between Notch-1 and embryo quality. Furthermore, only Notch-2 and Jagged-2 marginally correlated with zygote quality. CONCLUSION: The data of the present study indicated that evaluating the molecules in the Notch pathway in PCOS patients' cumulus cells provides a novel approach to predict the zygote and embryo quality. However, further studies on a larger population are needed to validate this finding.
Assuntos
Síndrome do Ovário Policístico , Células do Cúmulo , Feminino , Humanos , Transdução de Sinais , Injeções de Esperma Intracitoplásmicas , ZigotoRESUMO
Spinal cord injury (SCI) is a devastating condition with a growing incidence in developing countries. The activity of inflammasome complexes initiates neuroinflammation, which is a key player in SCI pathogenesis. Here, NLRP1, NLRP3, and absent in melanoma 2 (AIM2) inflammasome complexes were assessed in the contusive (T6) SCI rats for their expression profiles and their response to hormonal therapy (10 mg/kg melatonin or 25 µg/kg 17ß-estradiol [E2] every 12 h until 72 h). Two phases was considered in this study: the dominant time of inflammasome activation, which was 72 h post-SCI and the response from each complex to hormonal therapy at this time. Gene and protein expressions of NLRP1, NLRP3, AIM2, ASC, and caspase-1 were evaluated by real-time PCR (for gene analysis), western blot, and immunohistochemistry (IHC), and biochemical presence of IL-18 and IL-1ß in spinal cord tissue homogenates was analyzed by enzyme-linked immunosorbent assay (ELISA). The whole inflammasome complexes showed high expressions in the SCI group, while after hormonal therapy, these alterations were counteracted, which were more conspicuous for the NLRP1 and NLRP3. Melatonin had no predilection over E2 for such effect. Finally, the expression profile of signaling related to the synthesis (TLR4/NF-κB) and activation (NADPH oxidase 2 [NOX2]/TXNIP) of inflammasome complexes was surveyed, and there were low activities for the two pathways in SCI rats that underwent hormone therapy. From the findings, it is concluded that both melatonin and E2 are efficient to target inflammasome activation in the SCI rats.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismos da Medula Espinal/genética , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that leads to disability in middle-aged individuals. High rates of apoptosis and inappropriate homing are limitations for the application of stem cells in cell therapy. Preconditioning of bone marrow mesenchymal stem cells (BMSCs) with stromal cell-derived factor 1α (SDF-1α), also called C-X-C motif chemokine 12 (CXCL12), is an approach for improving the functional features of the cells. The aim of this study was to investigate the therapeutic efficacy of intranasal delivery of SDF-1α preconditioned BMSCs in the cuprizone-induced chronically demyelinated mice model. BMSCs were isolated, cultured, and preconditioned with SDF-1α. Then, intranasal delivery of the preconditioned cells was performed in the C57BL/6 mice receiving cuprizone for 12 weeks. Animals were killed at 30 days after cell delivery. SDF-1α preconditioning increased C-X-C chemokine receptor type 4 (CXCR4) expression on the surface of BMSCs, improved survival of the cells, and decreased their apoptosis in vitro. SDF-1α preconditioning also improved CXCL12 level within the brain, and enhanced spatial learning and memory (assessed by Morris water maze [MWM]), and myelination (assessed by Luxol fast blue [LFB] and transmission electron microscopy [TEM]). In addition, preconditioning of BMSCs with SDF-1α reduced the protein expressions of glial fibrillary acidic protein and ionized calcium-binding adapter molecule (Iba-1) and increased the expressions of oligodendrocyte lineage transcription factor-2 (Olig-2) and adenomatous polyposis coli (APC), evaluated by immunofluorescence. The results showed the efficacy of intranasal delivery of SDF-1α-preconditioned BMSCs for improving remyelination in the cuprizone model of MS.
Assuntos
Quimiocina CXCL12/administração & dosagem , Cuprizona/toxicidade , Modelos Animais de Doenças , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Esclerose Múltipla/terapia , Remielinização , Administração Intranasal , Animais , Movimento Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Monoaminoxidase/toxicidade , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Condicionamento Pré-TransplanteRESUMO
Stroke imposes a long-term neurological disability with limited effective treatments available for neuronal recovery. Transplantation of neural stem cells (NSCs) is reported to improve functional outcomes in the animal models of brain ischemia. However, the use of cell therapy is accompanied by adverse effects, so research is growing to use cell-free extracts such as extracellular vesicles (EVs) for targeting brain diseases. In the current study, male Wistar albino rats (20 months old) were subjected to middle cerebral artery occlusion (MCAO). Then, EVs (30 µg) were injected at 2 hours after stroke onset via an intracerebroventricular (ICV) route. Measurements were done at day 7 post-MCAO. EVs administration reduced lesion volume and steadily improved spontaneous locomotor activity. EVs administration also reduced microgliosis (ionized calcium-binding adaptor molecule 1 (Iba1)+ cells) and apoptotic (terminal-deoxynucleotidyl transferase mediated nick end labelling [TUNEL]) positive cells and increased neuronal survival (neuronal nuclear (NeuN)+ cells) in the ischemic boundary zone (IBZ). However, it had no effect on neurogenesis within the sub-ventricular zone (SVZ) but decreased cellular migration toward the IBZ (doublecortin (DCX)+ cells). The results of this study showed neuroprotective and restorative mechanisms of NSC-EVs administration, which may offer new avenues for therapeutic intervention of brain ischemia. SIGNIFICANCE OF THE STUDY: Based on our results, EVs administration can effectively reduce microglial density and neuronal apoptosis, thereby steadily improves functional recovery after MCAO. These findings provide the beneficial effect of NSC-EVs as a new biological treatment for stroke.
Assuntos
Vesículas Extracelulares , Infarto da Artéria Cerebral Média , Células-Tronco Neurais/metabolismo , Neuroproteção , Acidente Vascular Cerebral , Animais , Modelos Animais de Doenças , Proteína Duplacortina , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Vesículas Extracelulares/transplante , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/terapia , Masculino , Células-Tronco Neurais/patologia , Ratos , Ratos Wistar , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/terapiaRESUMO
CD8+ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune-resistance. Cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8 + T cell-mediated antitumor immune responses. Thus, CD8 + T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8 + T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4 + T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so-called infiltrated-inflamed [I-I] TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8 + T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death-1 receptor (PD-1)-ligand (PD-L1) and CTL-associated antigen 4 (CTLA-4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8 + T cells and renewing their priming, respectively, and thereby eliminating antigen-expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias/terapia , Linfócitos T Citotóxicos/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/efeitos adversos , Comunicação Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Imunoterapia/efeitos adversos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Microambiente TumoralRESUMO
Regulatory T cells (Tregs) represent a low number of T-cell population under normal conditions, and they play key roles for maintaining immune system in homeostasis. The number of these cells is extensively increased in nearly all cancers, which is for dampening responses from immune system against cancer cells, metastasis, tumor recurrence, and treatment resistance. The interesting point is that apoptotic Tregs are stronger than their live counterparts for suppressing responses from immune system. Tregs within the tumor microenvironment have extensive positive cross-talks with other immunosuppressive cells including cancer-associated fibroblasts, cancer cells, macrophage type 2 cells, and myeloid-derived suppressor cells, and they have negative interactions with immunostimulatory cells including cytotoxic T lymphocytes (CTL) and natural killer cells. A wide variety of markers are expressed in Tregs, among them forkhead box P3 (FOXP3) is the most specific marker and the master regulator of these cells. Multiple signals are activated by Tregs including transforming growth factor-ß, signal transducer and activator of transcription, and mTORC1. Treg reprogramming from an immunosuppressive to immunostimulatory proinflammatory phenotype is critical for increasing the efficacy of immunotherapy. This would be applicable through selective suppression of tumor-bearing receptors in Tregs, including FOXP3, programmed death-1, T-cell immunoglobulin mucin-3, and CTL-associated antigen-4, among others. Intratumoral Tregs can also be targeted by increasing the ratio for CTL/Treg.
Assuntos
Proteínas de Neoplasias/genética , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Fibroblastos Associados a Câncer/imunologia , Fatores de Transcrição Forkhead/genética , Humanos , Células Matadoras Naturais/imunologia , Macrófagos/imunologia , Células Supressoras Mieloides/imunologia , Metástase Neoplásica , Proteínas de Neoplasias/imunologia , Neoplasias/genética , Neoplasias/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/patologiaRESUMO
Cancer stem cells (CSCs) are self-renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor-type dependent. The transition between CSCs with cancer cells and other non-CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer-associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non-CSCs toward attaining a CSC-like phenotype. WNT/ß-catenin, transforming growth factor-ß, Hedgehog, and Notch are important signals for maintaining self-renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non-CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens.
Assuntos
Fibroblastos Associados a Câncer/patologia , Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral/genética , Antineoplásicos/uso terapêutico , Fibroblastos Associados a Câncer/efeitos dos fármacos , Diferenciação Celular/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco/genética , Hipóxia Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
Transforming growth factor (TGF)-ß is a multitasking cytokine such that its aberrant expression is related to cancer progression and metastasis. TGF-ß is produced by a variety of cells within the tumor microenvironment (TME), and it is responsible for regulation of the activity of cells within this milieu. TGF-ß is a main inducer of epithelial-mesenchymal transition (EMT), immune evasion, and metastasis during cancer progression. TGF-ß exerts most of its functions by acting on TßRI and TßRII receptors in canonical (Smad-dependent) or noncanonical (Smad-independent) pathways. Members of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and nuclear factor κß are involved in the non-Smad TGF-ß pathway. TGF-ß acts by complex signaling, and deletion in one of the effectors in this pathway may influence the outcome in a diverse way by taking even an antitumor role. The stage and the type of tumor (contextual cues from cancer cells and/or the TME) and the concentration of TGF-ß are other important factors determining the fate of cancer (progression or repression). There are a number of ways for targeting TGF-ß signaling in cancer, among them the special focus is on TßRII suppression.
Assuntos
Carcinogênese/metabolismo , Neoplasias/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Microambiente Tumoral/fisiologiaRESUMO
Cyclooxygenase-2 (COX-2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo- and radiotherapy. COX-2 is released by cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX-2 induces cancer stem cell (CSC)-like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX-2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX-2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX-2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX-2 on cancer cells or its regulation. Members of mitogen-activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor-κß are main upstream modulators for COX-2 in cancer cells. COX-2 also has interactions with a number of hormones within the body. Inhibition of COX-2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX-2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX-2 inhibition also sensitizes cancer cells to treatments like radio- and chemotherapy. Chemotherapeutic agents adversely induce COX-2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX-2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer.