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3.
Biochem Pharmacol ; 208: 115378, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36513141

RESUMO

Understanding the mechanisms regulating PD-L1 expression in hepatocellular carcinoma (HCC) is important to improve the response rate to PD-1/PD-L1 blockade therapy. Here, we show that DKK1 expression is positively associated with PD-L1 expression and inversely correlated with CD8+ T cell infiltration in human HCC tumor specimens. In a subcutaneous xenograft tumor model, overexpression of DKK1 significantly promotes tumor growth, tumoral PD-L1 expression, but reduces tumoral CD8+ T cell infiltration; whereas knockdown of DKK1 has opposite effects. Moreover, enforced expression of DKK1 dramatically promotes PD-L1 expression, Akt activation, ß-catenin phosphorylation and total protein expression in HCC cells. By contrast, knockdown of DKK1 inhibits all, relative to controls. In addition, CKAP4 depletion, Akt inhibition, or ß-catenin depletion remarkably abrogates DKK1 overexpression-induced transcriptional expression of PD-L1 in HCC cells. Reconstituted expression of the active Akt1 largely increased PD-L1 transcriptional expression in HCC cells. Similarly, expression of WT ß-catenin, but not the phosphorylation-defective ß-catenin S552A mutant, significantly promotes PD-L1 expression. Correlation analysis of human HCC tumor specimens further revealed that DKK1 and PD-L1 expression were positively correlated with p-ß-catenin expression. Together, our findings revealed that DKK1 promotes PD-L1 expression through the activation of Akt/ß-catenin signaling, providing a potential strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade therapy in HCC patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , beta Catenina/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Neoplasias Hepáticas/metabolismo , Receptor de Morte Celular Programada 1 , Proteínas Proto-Oncogênicas c-akt , Evasão Tumoral
4.
Int J Mol Sci ; 23(23)2022 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-36499125

RESUMO

Human gamma-delta (γδ) T cells are a heterogeneous cell population that bridges the gap between innate and acquired immunity. They are involved in a variety of immunological processes, including tumor escape mechanisms. However, by being prolific cytokine producers, these lymphocytes also participate in antitumor cytotoxicity. Which one of the two possibilities takes place depends on the tumor microenvironment (TME) and the subpopulation of γδ T lymphocytes. The aim of this paper is to summarize existing knowledge about the phenotype and dual role of γδ T cells in cancers, including ovarian cancer (OC). OC is the third most common gynecological cancer and the most lethal gynecological malignancy. Anticancer immunity in OC is modulated by the TME, including by immunosuppressive cells, cytokines, and soluble factors. Immune cells are exposed in the TME to many signals that determine their immunophenotype and can manipulate their functions. The significance of γδ T cells in the pathophysiology of OC is enigmatic and remains to be investigated.


Assuntos
Neoplasias , Linfócitos T , Humanos , Receptores de Antígenos de Linfócitos T gama-delta , Imunidade Adaptativa , Microambiente Tumoral , Evasão Tumoral , Citocinas , Neoplasias/patologia
5.
Int J Mol Sci ; 23(23)2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36499265

RESUMO

Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability and greater mutation rates, which may result in the creation of neoantigens and enhanced immunogenicity, are additional characteristics of this breast cancer type. Clinical outcome is poor due to early age of onset, high metastatic potential, and increased likelihood of distant recurrence. Consequently, efforts to elucidate molecular mechanisms of breast cancer development, progression, and metastatic spread have been initiated to improve treatment options and improve outcomes for these patients. The extremely complex and heterogeneous tumor immune microenvironment is made up of several cell types and commonly possesses disorganized gene expression. Altered signaling pathways are mainly associated with mutated genes including p53, PIK3CA, and MAPK, and which are positively correlated with genes regulating immune response. Of note, particular immunity-associated genes could be used in prognostic indexes to assess the most effective management. Recent findings highlight the fact that long non-coding RNAs also play an important role in shaping tumor microenvironment formation, and can mediate tumor immune evasion. Identification of molecular signatures, through the use of multi-omics approaches, and effector pathways that drive early stages of the carcinogenic process are important steps in developing new strategies for targeted cancer treatment and prevention. Advances in immunotherapy by remodeling the host immune system to eradicate tumor cells have great promise to lead to novel therapeutic strategies. Current research is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or natural killer cell therapy. Targeted therapies may improve therapeutic response, eliminate therapeutic resistance, and improve overall patient survival. In the future, these evolving advancements should be implemented for personalized medicine and state-of-art management of cancer patients.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Heterogeneidade Genética , Imunoterapia , Evasão Tumoral/genética
6.
J Immunother Cancer ; 10(12)2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36517082

RESUMO

Cancer-related deaths are mainly caused by metastatic spread of tumor cells from the primary lesion to distant sites via the blood circulation. Understanding the mechanisms of blood-borne tumor cell dissemination by the detection and molecular characterization of circulating tumor cells (CTCs) in the blood of patients with cancer has opened a new avenue in cancer research. Recent technical advances have enabled a comprehensive analysis of the CTCs at the genome, transcriptome and protein level as well as first functional studies using patient-derived CTC cell lines. In this review, we describe and discuss how research on CTCs has yielded important insights into the biology of cancer metastasis and the response of patients with cancer to therapies directed against metastatic cells. Future investigations will show whether CTCs leaving their primary site are more vulnerable to attacks by immune effector cells and whether cancer cell dissemination might be the 'Achilles heel' of metastatic progression. Here, we focus on the lessons learned from CTC research on the biology of cancer metastasis in patients with particular emphasis on the interactions of CTCs with the immune system. Moreover, we describe and discuss briefly the potential and challenges for implementing CTCs into clinical decision-making including detection of minimal residual disease, monitoring efficacies of systemic therapies and identification of therapeutic targets and resistance mechanisms.


Assuntos
Células Neoplásicas Circulantes , Humanos , Evasão Tumoral , Biologia
7.
Nat Commun ; 13(1): 6951, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376293

RESUMO

Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.


Assuntos
Antígeno B7-H1 , Neoplasias , Animais , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Glicosilação , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , Evasão Tumoral , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
8.
Biomed Pharmacother ; 156: 113917, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411610

RESUMO

Tumour metabolism has gradually come to be regarded as a key target to prevent tumour growth and metastasis. The unique metabolic characteristics of tumours enable them to maintain self-proliferation in abnormal environments. In recent years, the necessity of hypoxia in the tumour microenvironment has been gradually recognized, and hypoxia-induced tumour metabolites are also regarded as key therapeutic targets. How these hypoxia-related metabolites support tumour development, how to regulate the malignant process of tumours, and how to prevent tumour immune escape have become urgent problems that need to be solved. In this review, we summarize the characteristic tumour regulation of hypoxia-related metabolites and the mechanisms that promote immune escape of tumours. Finally, we summarize the relevant targeted inhibitors in an attempt to provide some novel therapeutic insights.


Assuntos
Hipóxia , Neoplasias , Humanos , Hipóxia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Microambiente Tumoral , Evasão Tumoral
9.
Cancer Discov ; 12(12): 2722, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36239520

RESUMO

Antigen density and tumor control are reduced after CAR-NK cell therapy by CAR-activated trogocytosis.


Assuntos
Neoplasias , Evasão Tumoral , Humanos , Trogocitose , Células Matadoras Naturais , Imunoterapia Adotiva , Neoplasias/terapia
11.
Nat Commun ; 13(1): 6308, 2022 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-36274066

RESUMO

Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Neoplasias Ósseas , Antígeno CD47 , Osteossarcoma , Animais , Camundongos , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Antígeno CD47/genética , Antígeno CD47/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Glutamina/metabolismo , Interleucina-18 , Leucina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fagocitose/genética , Evasão Tumoral/genética , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo
12.
J Hematol Oncol ; 15(1): 153, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284349

RESUMO

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.


Assuntos
Antígenos B7 , Neoplasias , Humanos , Imunoterapia/métodos , Neoplasias/terapia , Evasão Tumoral , Microambiente Tumoral
13.
Cell Immunol ; 382: 104615, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36228388

RESUMO

The role and regulation of innate immune cells is poorly understood in B-cell non-Hodgkin lymphoma (NHL). As natural killer (NK) cells, helper innate lymphoid cells (ILCs) are lymphocytes endowed with either anti- or pro-tumour activity and involved in inflammatory processes. In our ex vivo analysis of NK cells and ILCs from NHL patients, we observed that, in comparison to healthy donors (HD), the frequency of the cytotoxic subset of NK cells, the CD16+ NK, decreased in patients' peripheral blood. In general, circulating NK cells showed a pro-tumorigenic phenotype, while ILCs displayed a more activated/cytotoxic phenotype. Conversely, at the tumour site, in patients' lymph nodes, ILCs showed a low expression of granzyme.In vitromixed lymphocyte-tumour cell cultures with HD PBMCs and NHL cell lines demonstrated that ILC cytotoxic potential was lowered by the presence of tumour cells but, in the absence of T regulatory cells (Tregs), their cytolytic potential was recovered. Our data shed novel light on dysfunctional innate immunity in NHL. We suggest a new mechanism of tumour immuno-escape based on the reduction of cell cytotoxicity involving ILCs and likely controlled by Tregs.


Assuntos
Antineoplásicos , Linfoma não Hodgkin , Neoplasias , Humanos , Evasão Tumoral , Imunidade Inata , Linfócitos , Células Matadoras Naturais , Neoplasias/patologia , Linfoma não Hodgkin/patologia
14.
Cancer Immunol Res ; 10(12): 1506-1524, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36206576

RESUMO

Tumor-associated macrophages (TAM) have key functions in promoting a suppressive tumor immune microenvironment (TIME) and immune evasion, which largely limit treatment effects of immune-checkpoint inhibitors (ICI) in different cancers, including gastric cancer. Dickkopf-1 (DKK1) is associated with tumor progression and has been shown to negatively regulate antitumor immunity, but the impact of DKK1 on the TIME remains incompletely understood. Here, we found that tumoral DKK1 expression is closely associated with worse survival and a suppressive TIME in gastric cancer patients. Results from in vitro coculture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting antitumor responses of CD8+ T cells and natural killer (NK) cells. In vivo DKK1 blockade in syngeneic gastric cancer mouse models reprogramed TAMs to restore the immune activity in the TIME and triggered significant tumor regression. DKK1 blockade also directly reduced the growth of human gastric cancer tumors with high DKK1 expression in a xenograft model. Mechanistically, DKK1 interacted with cytoskeleton-associated protein 4 (CKAP4) on the macrophage surface and activated downstream PI3K-AKT signaling, which contributed to immune suppression. TAM reprogramming by DKK1 blockade also augmented the efficacy of programmed cell death protein-1 (PD-1) blockade in gastric cancer models. Therefore, our study provides novel insights into the role of DKK1 on tumor-intrinsic, innate, and adaptive antitumor immunity modulation and suggests that DKK1 is a promising immunotherapeutic target for enhanced PD-1 blockade therapy in gastric cancer.


Assuntos
Neoplasias Gástricas , Evasão Tumoral , Camundongos , Animais , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Microambiente Tumoral , Macrófagos , Linhagem Celular Tumoral , Peptídeos e Proteínas de Sinalização Intercelular
15.
Mol Cell ; 82(20): 3901-3918.e7, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36206767

RESUMO

How cancer-associated chromatin abnormalities shape tumor-immune interaction remains incompletely understood. Recent studies have linked DNA hypomethylation and de-repression of retrotransposons to anti-tumor immunity through the induction of interferon response. Here, we report that inactivation of the histone H3K36 methyltransferase NSD1, which is frequently found in squamous cell carcinomas (SCCs) and induces DNA hypomethylation, unexpectedly results in diminished tumor immune infiltration. In syngeneic and genetically engineered mouse models of head and neck SCCs, NSD1-deficient tumors exhibit immune exclusion and reduced interferon response despite high retrotransposon expression. Mechanistically, NSD1 loss results in silencing of innate immunity genes, including the type III interferon receptor IFNLR1, through depletion of H3K36 di-methylation (H3K36me2) and gain of H3K27 tri-methylation (H3K27me3). Inhibition of EZH2 restores immune infiltration and impairs the growth of Nsd1-mutant tumors. Thus, our work uncovers a druggable chromatin cross talk that regulates the viral mimicry response and enables immune evasion of DNA hypomethylated tumors.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Histona Metiltransferases , Evasão Tumoral , Animais , Camundongos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Cromatina , Metilação de DNA , Neoplasias de Cabeça e Pescoço/genética , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Interferons/genética , Proteínas Nucleares/metabolismo , Receptores de Interferon/genética , Retroelementos , Evasão Tumoral/genética
16.
Biochem J ; 479(20): 2219-2260, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36305711

RESUMO

Through activation of immune cells, the immune system is responsible for identifying and destroying infected or otherwise damaged cells including tumorigenic cells that can be recognized as foreign, thus maintaining homeostasis. However, tumor cells have evolved several mechanisms to avoid immune cell detection and killing, resulting in tumor growth and progression. In the tumor microenvironment, tumor infiltrating immune cells are inactivated by soluble factors or tumor promoting conditions and lose their effects on tumor cells. Analysis of signaling and crosstalk between immune cells and tumor cells have helped us to understand in more detail the mechanisms of tumor immune evasion and this forms basis for drug development strategies in the area of cancer immunotherapy. In this review, we will summarize the dominant signaling networks involved in immune escape and describe the status of development of therapeutic strategies to target tumor immune evasion mechanisms with focus on how the tumor microenvironment interacts with T cells.


Assuntos
Neoplasias , Evasão Tumoral , Humanos , Microambiente Tumoral , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Linfócitos T , Evasão da Resposta Imune
17.
Cell ; 185(21): 4038-4038.e1, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36240741

RESUMO

In the tumor microenvironment, immune cells and tumor cells interact in a process called cancer immunoediting, giving rise to changes in gene expression, metabolism, mutational burden, and cellularity in the tumor. This SnapShot compares endogenous versus therapy-induced cancer immunoediting and outlines the molecular and cellular characteristics of interactions that result in complete tumor regression versus tumor escape and progression. To view this SnapShot, open or download the PDF.


Assuntos
Neoplasias/imunologia , Microambiente Tumoral , Humanos , Mutação , Neoplasias/genética , Neoplasias/terapia , Evasão Tumoral
18.
Med Oncol ; 39(12): 183, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071295

RESUMO

Exosomes are a subgroup of extracellular vesicles generated by distinct cells. Tumor-derived extracellular vesicles convey immunological checkpoint molecules. TEXs as critical mediators in tumor development, metastasis, and immune escape have recently become the focus of scientific research. Exosomes are involved in the regulation of the immune system. Exosomes interact with target cells in the tumor microenvironment, changing their function based on the cargo they contain. Exosomal immune checkpoints might be exploited to track tumor immune evasion, treatment response, and patient prognosis while enhancing tumor cell proliferation and spread. This review focuses on tumor-derived exosomes, their immunosuppressive effects in mice models, and their role in cancer immunotherapy. Exosomes are being studied as possible cancer vaccines, with numerous uses in tumor immunotherapy. Exosomes can carry chemotherapeutics, siRNA, and monoclonal antibodies. Exosomes produced by macrophages might be used to treat cancer. These and other clinical consequences provide new doors for cancer treatment.


Assuntos
Exossomos , Neoplasias , Animais , Exossomos/genética , Imunoterapia , Camundongos , Neoplasias/tratamento farmacológico , Evasão Tumoral , Microambiente Tumoral
19.
Mol Cancer ; 21(1): 176, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071523

RESUMO

Immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized the treatment of many types of cancer, particularly advanced-stage cancers. Nevertheless, although a subset of patients experiences dramatic and long-term disease regression in response to ICIs, most patients do not benefit from these treatments. Some may even experience cancer progression. Immune escape by tumor cells may be a key reason for this low response rate. N6-methyladenosine (m6A) is the most common type of RNA methylation and has been recognized as a critical regulator of tumors and the immune system. Therefore, m6A modification and related regulators are promising targets for improving the efficacy of tumor immunotherapy. However, the association between m6A modification and tumor immune escape (TIE) has not been comprehensively summarized. Therefore, this review summarizes the existing knowledge regarding m6A modifications involved in TIE and their potential mechanisms of action. Moreover, we provide an overview of currently available agents targeting m6A regulators that have been tested for their elevated effects on TIE. This review establishes the association between m6A modifications and TIE and provides new insights and strategies for maximizing the efficacy of immunotherapy by specifically targeting m6A modifications involved in TIE.


Assuntos
Neoplasias , Evasão Tumoral , Adenosina/análogos & derivados , Humanos , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , RNA , Evasão Tumoral/genética
20.
Front Immunol ; 13: 990463, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36131911

RESUMO

Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells which are abnormally accumulated during the differentiation of myeloid cells. Immunosuppression is the main functional feature of MDSCs, which inhibit T cell activity in the tumor microenvironment (TME) and promote tumoral immune escape. The main principle for immunotherapy is to modulate, restore, and remodel the plasticity and potential of immune system to have an effective anti-tumor response. In the TME, MDSCs are major obstacles to cancer immunotherapy through reducing the anti-tumor efficacy and making tumor cells more resistant to immunotherapy. Therefore, targeting MDSCs treatment becomes the priority of relevant studies and provides new immunotherapeutic strategy for cancer treatment. In this review, we mainly discuss the functions and mechanisms of MDSCs as well as their functional changes in the TME. Further, we review therapeutic effects of immunotherapy against MDSCs and potential breakthroughs regarding immunotherapy targeting MDSCs and immune checkpoint blockade (ICB) immunotherapy.


Assuntos
Células Supressoras Mieloides , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Evasão Tumoral , Microambiente Tumoral
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