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1.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205019

RESUMO

Clinically, different approaches are adopted worldwide for the treatment of cancer, which still ranks second among all causes of death. Immunotherapy for cancer treatment has been the focus of attention in recent years, aiming for an eventual antitumoral effect through the immune system response to cancer cells both prophylactically and therapeutically. The application of nanoparticulate delivery systems for cancer immunotherapy, which is defined as the use of immune system features in cancer treatment, is currently the focus of research. Nanomedicines and nanoparticulate macromolecule delivery for cancer therapy is believed to facilitate selective cytotoxicity based on passive or active targeting to tumors resulting in improved therapeutic efficacy and reduced side effects. Today, with more than 55 different nanomedicines in the market, it is possible to provide more effective cancer diagnosis and treatment by using nanotechnology. Cancer immunotherapy uses the body's immune system to respond to cancer cells; however, this may lead to increased immune response and immunogenicity. Selectivity and targeting to cancer cells and tumors may lead the way to safer immunotherapy and nanotechnology-based delivery approaches that can help achieve the desired success in cancer treatment.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Sistema Imunitário/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Imunoterapia , Nanopartículas , Neoplasias/imunologia
2.
Nat Commun ; 12(1): 4077, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210970

RESUMO

Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fatores Imunológicos/metabolismo , Imunoterapia Adotiva/métodos , Microbiota/fisiologia , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Butiratos/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Imunoterapia , Interferon gama , Subunidade alfa de Receptor de Interleucina-2 , Megasphaera , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Receptores Acoplados a Proteínas G/genética , Fator de Necrose Tumoral alfa
3.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200284

RESUMO

Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties. Disialylated gangliosides GD2 and GD3 are considered as markers of neuroectoderm origin in tumors, whereas fucosyl-GM1 is expressed in very few normal tissues but overexpressed in a variety of cancers, especially in small cell lung carcinoma. These gangliosides are absent in most normal adult tissues, making them targets of interest in immuno-oncology. Passive and active immunotherapy strategies have been developed, and have shown promising results in clinical trials. In this review, we summarized the current knowledge on GD2, GD3, and fucosyl-GM1 expression in health and cancer, their biosynthesis pathways in the Golgi apparatus, and their biological roles. We described how their overexpression can affect intracellular signaling pathways, increasing the malignant phenotypes of cancer cells, including their metastatic potential and invasiveness. Finally, the different strategies used to target these tumor-associated gangliosides for immunotherapy were discussed, including the use and development of monoclonal antibodies, vaccines, immune system modulators, and immune effector-cell therapy, with a special focus on adoptive cellular therapy with T cells engineered to express chimeric antigen receptors.


Assuntos
Anticorpos Monoclonais/farmacologia , Biomarcadores Tumorais/metabolismo , Glicoesfingolipídeos/antagonistas & inibidores , Glicoesfingolipídeos/metabolismo , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Animais , Glicoesfingolipídeos/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais
5.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207286

RESUMO

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's "Seed and Soil" hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor ß (TGFß), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.


Assuntos
Neoplasias/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Animais , Diferenciação Celular , Humanos , Imunoterapia/métodos , Metástase Neoplásica , Neoplasias/imunologia , Neoplasias/terapia , Macrófagos Associados a Tumor/patologia
6.
Nat Commun ; 12(1): 4300, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262035

RESUMO

Common fragile sites (CFSs) are specific breakage-prone genomic regions and are present frequently in cancer cells. The (E2-independent) E3 ubiquitin-conjugating enzyme FATS (fragile site-associated tumor suppressor) has antitumor activity in cancer cells, but the function of FATS in immune cells is unknown. Here, we report a function of FATS in tumor development via regulation of tumor immunity. Fats-/- mice show reduced subcutaneous B16 melanoma and H7 pancreatic tumor growth compared with WT controls. The reduced tumor growth in Fats-/- mice is macrophage dependent and is associated with a phenotypic shift of macrophages within the tumor from tumor-promoting M2-like to antitumor M1-like macrophages. In addition, FATS deficiency promotes M1 polarization by stimulating and prolonging NF-κB activation by disrupting NF-κB/IκBα negative feedback loops and indirectly enhances both CD4+ T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) adaptive immune responses to promote tumor regression. Notably, transfer of Fats-/- macrophages protects mice against B16 melanoma. Together, these data suggest that FATS functions as an immune regulator and is a potential target in cancer immunotherapy.


Assuntos
Macrófagos/imunologia , Neoplasias/imunologia , Proteínas Supressoras de Tumor/imunologia , Animais , Linhagem Celular Tumoral , Humanos , Imunoterapia , Ativação de Macrófagos , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Proteínas Supressoras de Tumor/deficiência
7.
Nat Commun ; 12(1): 4299, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262038

RESUMO

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO3-assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Nanomedicina/métodos , Neoplasias/terapia , Ablação por Radiofrequência , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Carbonato de Cálcio/química , Carbonato de Cálcio/uso terapêutico , Catálise , Linhagem Celular Tumoral , Terapia Combinada , Ferroptose/efeitos dos fármacos , Hemina/química , Hemina/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoxigenase/química , Lipoxigenase/uso terapêutico , Camundongos , Metástase Neoplásica , Neoplasia Residual , Neoplasias/imunologia , Neoplasias/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/uso terapêutico , Coelhos
8.
Nat Commun ; 12(1): 4405, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285232

RESUMO

Stimulator of interferon genes (STING) promotes anti-tumour immunity by linking innate and adaptive immunity, but it remains unclear how intratumoural treatment with STING agonists yields anti-tumour effects. Here we demonstrate that intratumoural injection of the STING agonist cGAMP induces strong, rapid, and selective apoptosis of tumour endothelial cells (ECs) in implanted LLC tumour, melanoma and breast tumour, but not in spontaneous breast cancer and melanoma. In both implanted and spontaneous tumours, cGAMP greatly increases TNFα from tumour-associated myeloid cells. However, compared to spontaneous tumour ECs, implanted tumour ECs are more vulnerable to TNFα-TNFR1 signalling-mediated apoptosis, which promotes effective anti-tumour activity. The spontaneous tumour's refractoriness to cGAMP is abolished by co-treatment with AKT 1/2 inhibitor (AKTi). Combined treatment with cGAMP and AKTi induces extensive tumour EC apoptosis, leading to extensive tumour apoptosis and marked growth suppression of the spontaneous tumour. These findings propose an advanced avenue for treating primary tumours that are refractory to single STING agonist therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Membrana/agonistas , Neoplasias/tratamento farmacológico , Nucleotídeos Cíclicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunidade Inata/efeitos dos fármacos , Injeções Intralesionais , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neoplasias/patologia , Nucleotídeos Cíclicos/uso terapêutico , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207500

RESUMO

The ability of tumor cells to evade the immune system is one of the main challenges we confront in the fight against cancer. Multiple strategies have been developed to counteract this situation, including the use of immunostimulant molecules that play a key role in the anti-tumor immune response. Such a response needs to be tumor-specific to cause as little damage as possible to healthy cells and also to track and eliminate disseminated tumor cells. Therefore, the combination of immunostimulant molecules and tumor-associated antigens has been implemented as an anti-tumor therapy strategy to eliminate the main obstacles confronted in conventional therapies. The immunostimulant 4-1BBL belongs to the tumor necrosis factor (TNF) family and it has been widely reported as the most effective member for activating lymphocytes. Hence, we will review the molecular, pre-clinical, and clinical applications in conjunction with tumor-associated antigens in antitumor immunotherapy, as well as the main molecular pathways involved in this association.


Assuntos
Ligante 4-1BB/imunologia , Antígenos de Neoplasias/imunologia , Imunidade Inata , Ativação Linfocitária , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Animais , Humanos , Neoplasias/patologia , Neoplasias/terapia
10.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207762

RESUMO

Extracellular vesicles (EVs) play a key role in health and disease, including cancer. Tumors produce a mix of EVs differing in size, cellular origin, biogenesis and molecular content. Small EVs (sEV) or exosomes are a subset of 30-150 nm (virus-size) vesicles originating from the multivesicular bodies (MVBs) and carrying a cargo that in its content and topography approximates that of a parent cell. Tumor-derived exosomes (TEX) present in all body fluids of cancer patients, are considered promising candidates for a liquid tumor biopsy. TEX also mediate immunoregulatory activities: they maintain a crosstalk between the tumor and various non-malignant cells, including immunocytes. Effects that EVs exert on immune cells may be immunosuppressive or immunostimulatory. Here, we review the available data for TEX interactions with immunocytes, focusing on strategies that allow isolation from plasma and separation of TEX from sEV produced by non-malignant cells. Immune effects mediated by either of the subsets can now be distinguished and measured. The approach has allowed for the comparison of molecular and functional profiles of the two sEV fractions in plasma of cancer patients. While TEX carried an excess of immunosuppressive proteins and inhibited immune cell functions in vitro and in vivo, the sEV derived from non-malignant cells, including CD3(+)T cells, were variably enriched in immunostimulatory proteins and could promote functions of immunocytes. Thus, sEV in plasma of cancer patients are heterogenous, representing a complex molecular network which is not evident in healthy donors' plasma. Importantly, TEX appear to be able to reprogram functions of non-malignant CD3(+)T cells inducing them to produce CD3(+)sEV enriched in immunosuppressive proteins. Ratios of stimulatory/inhibitory proteins carried by TEX and by CD3(+)sEV derived from reprogrammed non-malignant cells vary broadly in patients and appear to negatively correlate with disease progression. Simultaneous capture from plasma and functional/molecular profiling of TEX and the CD3(+)sEV fractions allows for defining their role as cancer biomarkers and as monitors of cancer patients' immune competence, respectively.


Assuntos
Biomarcadores Tumorais/imunologia , Exossomos/imunologia , Tolerância Imunológica/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Humanos , Oncologia
11.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209132

RESUMO

The metabolic requirements and functions of cancer and normal tissues are vastly different. Due to the rapid growth of cancer cells in the tumor microenvironment, distorted vasculature is commonly observed, which creates harsh environments that require rigorous and constantly evolving cellular adaption. A common hallmark of aggressive and therapeutically resistant tumors is hypoxia and hypoxia-induced stress markers. However, recent studies have identified alterations in a wide spectrum of metabolic pathways that dictate tumor behavior and response to therapy. Accordingly, it is becoming clear that metabolic processes are not uniform throughout the tumor microenvironment. Metabolic processes differ and are cell type specific where various factors promote metabolic heterogeneity within the tumor microenvironment. Furthermore, within the tumor, these metabolically distinct cell types can organize to form cellular neighborhoods that serve to establish a pro-tumor milieu in which distant and spatially distinct cellular neighborhoods can communicate via signaling metabolites from stroma, immune and tumor cells. In this review, we will discuss how biochemical interactions of various metabolic pathways influence cancer and immune microenvironments, as well as associated mechanisms that lead to good or poor clinical outcomes.


Assuntos
Neoplasias/imunologia , Óxido Nítrico/imunologia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Neoplasias/patologia
12.
Int J Nanomedicine ; 16: 4693-4712, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267518

RESUMO

Benefiting from the rapid development of nanotechnology, photodynamic therapy (PDT) is arising as a novel non-invasive clinical treatment for specific cancers, which exerts direct efficacy in destroying primary tumors by generating excessive cytotoxic reactive oxygen species (ROS). Notably, PDT-induced cell death is related to T cell-mediated antitumor immune responses through induction of immunogenic cell death (ICD). However, ICD elicited via PDT is not strong enough and is limited by immunosuppressive tumor microenvironment (ITM). Therefore, it is necessary to improve PDT efficacy through enhancing ICD with the combination of synergistic tumor therapies. Herein, the recent progress of nanomaterials-based PDT combined with chemotherapy, photothermal therapy, radiotherapy, and immunotherapy, employing ICD-boosted treatments is reviewed. An outlook about the future application in clinics of nanomaterials-based PDT strategies is also mentioned.


Assuntos
Morte Celular Imunogênica/efeitos dos fármacos , Nanomedicina/métodos , Nanoestruturas , Fotoquimioterapia/métodos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia
13.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204326

RESUMO

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.


Assuntos
Imunomodulação , Neoplasias/imunologia , Neoplasias/metabolismo , Esfingolipídeos/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Comunicação Celular , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lisofosfolipídeos/metabolismo , Neoplasias/terapia , Transdução de Sinais , Esfingolipídeos/química , Esfingolipídeos/imunologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Resultado do Tratamento
14.
Anticancer Res ; 41(7): 3247-3252, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230118

RESUMO

Cancer immunotherapy is an evolving field of research. Cytokines have been conceptualized as an anticancer therapy for longer than most other cancer immunotherapy modalities. Yet, to date, only two cytokines are FDA-approved: IFN-α and IL-2. Despite the initial breakthrough, both agents have been superseded by other, more efficacious agents such as immune checkpoint inhibitors. Several issues persist with cytokine-based cancer therapies; these are broadly categorised into a) high toxicity and b) low efficacy. Despite the only moderate benefits with early cytokine-based cancer therapies, advances in molecular engineering, genomics, and molecular analysis hold promise to optimise and reinstate cytokine-based therapies in future clinical practice. This review considers five important concepts for the successful clinical application of cytokine-based cancer therapies including: (i) improving pharmacokinetics and pharmacodynamics, (ii) improving local administration strategies, (iii) understanding context-dependent interactions in the tumour-microenvironment, (iv) elucidating the role of genetic polymorphisms, and (v) optimising combination therapies. IL-10 has been the focus of attention in recent years and is discussed herein as an example.


Assuntos
Citocinas/farmacologia , Citocinas/uso terapêutico , Interleucina-10/farmacologia , Interleucina-10/uso terapêutico , Neoplasias/imunologia , Neoplasias/terapia , Animais , Humanos , Imunoterapia/métodos , Polimorfismo Genético/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
15.
Anticancer Res ; 41(8): 3825-3831, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281842

RESUMO

BACKGROUND/AIM: The enzyme-linked immunospot (ELISPOT) assay is a well-established method used to evaluate the strength of T cell-mediated immune activity, and accepted as a standard functional immunological assay. Cytokine activity is a novel parameter reflecting spot size and intensity, which has not been used in ELISPOT assay before. MATERIALS AND METHODS: In the present study, from 113 ELISPOT assay data derived from previous clinical trials with dendritic cell vaccines, both spot number count and cytokine activity data for IFN-γ secretion were obtained using an ELISPOT reader. Comparing the new parameter cytokine activity with the existing parameter spot number, the feasibility of cytokine activity was investigated. RESULTS: There were no significant differences in sensitivity and specificity between spot number and cytokine activity among ELISPOT assay data from CMVpp65 and other antigen peptide-stimulated cytotoxic T lymphocytes. CONCLUSION: Although cytokine activity is a novel parameter unreported so far, it did not show any advantages in the evaluation T cell immune responses compared to the existing spot number parameter.


Assuntos
Citocinas/metabolismo , ELISPOT/métodos , Neoplasias/imunologia , Glioblastoma/imunologia , Humanos , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Melanoma/imunologia , Linfócitos T Citotóxicos/imunologia
16.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201758

RESUMO

Neutrophils-once considered as simple killers of pathogens and unexciting for cancer research-are now acknowledged for their role in the process of tumorigenesis. Neutrophils are recruited to the tumor microenvironment where they turn into tumor-associated neutrophils (TANs), and are able to initiate and promote tumor progression and metastasis. Conversely, anti-tumorigenic properties of neutrophils have been documented, highlighting the versatile nature and high pleiotropic plasticity of these polymorphonuclear leukocytes (PMN-L). Here, we dissect the ambivalent roles of TANs in cancer and focus on selected functional aspects that could be therapeutic targets. Indeed, the critical point of targeting TAN functions lies in the fact that an immunosuppressive state could be induced, resulting in unwanted side effects. A deeper knowledge of the mechanisms linked to diverse TAN functions in different cancer types is necessary to define appropriate therapeutic strategies that are able to induce and maintain an anti-tumor microenvironment.


Assuntos
Carcinogênese/patologia , Terapia de Alvo Molecular/métodos , Neoplasias/patologia , Neutrófilos/patologia , Microambiente Tumoral/imunologia , Animais , Carcinogênese/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neutrófilos/imunologia
17.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281293

RESUMO

Macrophages are one of the most important cells of the innate immune system and are known for their ability to engulf and digest foreign substances, including cellular debris and tumor cells. They can convert into tumor-associated macrophages (TAMs) when mature macrophages are recruited into the tumor microenvironment. Their role in cancer progression, metastasis, and therapy failure is of special note. The aim of this review is to understand how the presence of TAMs are both advantageous and disadvantageous in the immune system.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Macrófagos Associados a Tumor/imunologia , Animais , Terapia Combinada , Feminino , Humanos , Imunidade Inata , Imunoterapia/métodos , Masculino , Modelos Imunológicos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/classificação
18.
Aging (Albany NY) ; 13(12): 16248-16266, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135128

RESUMO

Paxillin (PXN) is a protein involved in numerous physiological processes, and its presence is closely related to the occurrence and development of many types of tumors. However, no studies have analyzed PXN from a pan-cancer perspective. We analyzed PXN expression, immune cell infiltration, prognosis, and biological function across different types of tumors included in The Cancer Genome Atlas and Gene Expression Omnibus datasets. The results showed that expression of PXN varies in different tumors. Expression of PXN strongly correlated with prognosis in patients with tumors; higher PXN expression usually was linked to poor overall and disease-free survival. Expression of PXN in breast invasive carcinoma and lymphoid neoplasm diffuse large B-cell lymphoma was related to the degree of CD8+ T-cell infiltration, and infiltration of cancer-associated fibroblasts, such as kidney renal papillary cell carcinoma and brain lower-grade glioma, was also observed in other tumors. The results of pan-cancer analysis showed that abnormal PXN expression was related to poor prognosis, immune infiltration, and protein phosphorylation in different tumor types. Therefore, the PXN gene may become a potential biomarker of clinical tumor prognosis.


Assuntos
Neoplasias/imunologia , Paxilina/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Mutação/genética , Neoplasias/genética , Neoplasias/patologia , Paxilina/genética , Fosforilação , Prognóstico , Análise de Sobrevida
19.
Int J Biol Macromol ; 183: 2364-2375, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34111484

RESUMO

TANK-binding kinase 1 (TBK1) regulates various biological processes including, NF-κB signaling, immune response, autophagy, cell division, Ras-mediated oncogenesis, and AKT pro-survival signaling. Enhanced TBK1 activity is associated with autoimmune diseases and cancer, suggesting its role in therapeutic targeting of interferonopathies. In addition, dysregulation of TBK1 activity promotes several inflammatory disorders and oncogenesis. Structural and biochemical study reports provide the molecular process of TBK1 activation and recap the substrate selection about TBK1. This review summarizes recent findings on the molecular mechanisms by which TBK1 is involved in cancer signaling. The IKK-ε and TBK1 are together associated with inflammatory diseases by inducing type I IFNs. Furthermore, TBK1 signaling regulates radiation-induced epithelial-mesenchymal transition by controlling phosphorylation of GSK-3ß and expression of Zinc finger E-box-binding homeobox 1, suggesting, TBK1 could be targeted for radiotherapy-induced metastasis therapy. Despite a considerable increase in the list of TBK1 inhibitors, only a few has potential to control cancer. Among them, a compound BX795 is considered a potent and selective inhibitor of TBK1. We discussed the therapeutic potential of small-molecule inhibitors of TBK1, particularly those with high selectivity, which will enable further exploration in the therapeutic management of cancer and inflammatory diseases.


Assuntos
Neoplasias/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Autofagia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
20.
Med Oncol ; 38(8): 90, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34191146

RESUMO

During the COVID-19 pandemic, it is important to assure the safety and management of cancer patients. Despite preliminary studies revealed that patients with cancer are more susceptible to infection and have poorer prognosis than other infected patients without cancer, mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. So, we have some comments about the pathogenesis attributed to the COVID-19 disease and cancer relationship and determination of subgroups in this and oncoming studies. Variable effects of anticancer treatments on the patient's immune system are yet to be elucidated. On the other hand, the effect of SARS-CoV-2 virus on tumor microenvironment or immune responses in cancer is not yet fully proven. Very recently, Challenor and her colleague reported a case with classical Hodgkin lymphoma with stage IIIs disease, which went into remission without corticosteroid or immunochemotherapy. They assumed that the putative mechanisms of action include cross-reactivity of pathogen-specific T cells with tumor antigens and natural killer cell activation by inflammatory cytokines produced in response to infection. During the course of COVID-19 disease, immune checkpoint blockade effect might be induced naturally.


Assuntos
COVID-19/imunologia , Neoplasias/imunologia , SARS-CoV-2/imunologia , Reações Cruzadas , Citocinas/imunologia , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Ativação Linfocitária , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
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