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1.
Nature ; 609(7925): 174-182, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36002574

RESUMO

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.


Assuntos
Antígenos de Neoplasias , Neoplasias , Linfócitos T , Proteínas Ativadoras de ras GTPase , Animais , Antígenos de Neoplasias/imunologia , Medula Óssea , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Imunoterapia Adotiva , Leucemia/imunologia , Leucemia/patologia , Leucemia/terapia , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Ativadoras de ras GTPase/deficiência , Proteínas Ativadoras de ras GTPase/genética
2.
Science ; 377(6610): 1085-1091, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-35926007

RESUMO

The hypothalamic-pituitary (HP) unit can produce various hormones to regulate immune responses, and some of its downstream hormones or effectors are elevated in cancer patients. We show that the HP unit can promote myelopoiesis and immunosuppression to accelerate tumor growth. Subcutaneous implantation of tumors induced hypothalamus activation and pituitary α-melanocyte-stimulating hormone (α-MSH) production in mice. α-MSH acted on bone marrow progenitors to promote myelopoiesis, myeloid cell accumulation, immunosuppression, and tumor growth through its melanocortin receptor MC5R. MC5R peptide antagonist boosted antitumor immunity and anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Serum α-MSH concentration was elevated and correlated with circulating myeloid-derived suppressor cells in cancer patients. Our results reveal a neuroendocrine pathway that suppresses tumor immunity and suggest MC5R as a potential target for cancer immunotherapy.


Assuntos
Sistema Hipotálamo-Hipofisário , Tolerância Imunológica , Mielopoese , Neoplasias , alfa-MSH , Animais , Sistema Hipotálamo-Hipofisário/metabolismo , Camundongos , Mielopoese/imunologia , Neoplasias/imunologia , Receptores de Melanocortina/metabolismo , alfa-MSH/metabolismo
3.
Nat Commun ; 13(1): 5018, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028490

RESUMO

mTORC1 is hyperactive in multiple cancer types1,2. Here, we performed integrative analysis of single cell transcriptomic profiling, paired T cell receptor (TCR) sequencing, and spatial transcriptomic profiling on Tuberous Sclerosis Complex (TSC) associated tumors with mTORC1 hyperactivity, and identified a stem-like tumor cell state (SLS) linked to T cell dysfunction via tumor-modulated immunosuppressive macrophages. Rapamycin and its derivatives (rapalogs) are the primary treatments for TSC tumors, and the stem-like tumor cells showed rapamycin resistance in vitro, reminiscent of the cytostatic effects of these drugs in patients. The pro-angiogenic factor midkine (MDK) was highly expressed by the SLS population, and associated with enrichment of endothelial cells in SLS-dominant samples. Inhibition of MDK showed synergistic benefit with rapamycin in reducing the growth of TSC cell lines in vitro and in vivo. In aggregate, this study suggests an autocrine rapamycin resistance mechanism and a paracrine tumor survival mechanism via immune suppression adopted by the stem-like state tumor cells with mTORC1 hyperactivity.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina , Midkina , Neoplasias , Células-Tronco Neoplásicas , Microambiente Tumoral , Células Endoteliais , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Midkina/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Sirolimo , Serina-Treonina Quinases TOR , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor
4.
Cell Biol Int ; 46(10): 1557-1570, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35811438

RESUMO

A crucial component of the immune system are chemokiness. Chemokine's dysregulation has been linked to a number of pathological diseases. Recently, CXCL17, a chemokine belonging to the CXC subfamily, was identified. With regard to a number of physiological conditions and disorders, CXCL17 either has homeostatic or pathogenic effects. Some research suggests that CXCL17 is an orphan ligand, despite the fact that G protein-coupled receptor (GPR) 35 has been suggested as a possible receptor for CXCL17. Since CXCL17 is primarily secreted by mucosal epithelia, such as those in the digestive and respiratory tracts, under physiological circumstances, this chemokine is referred to as a mucosal chemokine. Macrophages and monocytes are the cells that express GPR35 and hence react to CXCL17. In homeostatic conditions, this chemokine has anti-inflammatory, antibacterial, and chemotactic properties. CXCL17 promotes angiogenesis, metastasis, and cell proliferation in pathologic circumstances like malignancies. However, other studies suggest that CXCL17 may have anti-tumor properties. Additionally, studies have shown that CXCL17 may have a role in conditions such as idiopathic pulmonary fibrosis, multiple sclerosis, asthma, and systemic sclerosis. Additionally, deregulation of CXCL17 in some diseases may serve as a biomarker for diagnosis and prognosis. Clarifying the underlying mechanism of CXCL17's activity in homeostatic and pathological situations may thus increase our understanding of its role and hold promise for the development of novel treatment strategies.


Assuntos
Quimiocinas CXC , Infecções , Inflamação , Neoplasias , Quimiocinas , Quimiocinas CXC/fisiologia , Humanos , Infecções/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Receptores Acoplados a Proteínas G
5.
Proc Natl Acad Sci U S A ; 119(31): e2203410119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35878026

RESUMO

Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide-major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicting potential toxicity. We performed multimodal immunopeptidomic analyses for human prostatic acid phosphatase (PAP), a well-recognized tissue antigen. Three physical methods, including mild acid elution, coimmunoprecipitation, and secreted MHC precipitation, were used to capture a thorough signature of PAP on HLA-A*02:01. Eleven PAP peptides that are potentially A*02:01-restricted were identified, including five predicted strong binders by NetMHCpan 4.0. Peripheral blood mononuclear cells (PBMCs) from more than 20 healthy donors were screened with the PAP peptides. Seven cognate TCRs were isolated which can recognize three distinct epitopes when expressed in PBMCs. One TCR shows reactivity toward cell lines expressing both full-length PAP and HLA-A*02:01. Our results show that a combined multimodal immunopeptidomic approach is productive in revealing target peptides and defining the cloned TCR sequences reactive with prostatic acid phosphatase epitopes.


Assuntos
Fosfatase Ácida , Antígenos de Neoplasias , Receptores de Antígenos de Linfócitos T , Fosfatase Ácida/metabolismo , Antígenos de Neoplasias/metabolismo , Epitopos , Antígenos HLA-A/metabolismo , Antígeno HLA-A2 , Humanos , Leucócitos Mononucleares , Neoplasias/imunologia , Peptídeos , Receptores de Antígenos de Linfócitos T/metabolismo
6.
Proc Natl Acad Sci U S A ; 119(31): e2205469119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35895684

RESUMO

T regulatory (Treg) cells are essential for self-tolerance whereas they are detrimental for dampening the host anti-tumor immunity. How Treg cells adapt to environmental signals to orchestrate their homeostasis and functions remains poorly understood. Here, we identified that transcription factor EB (TFEB) is induced by host nutrition deprivation or interleukin (IL)-2 in CD4+ T cells. The loss of TFEB in Treg cells leads to reduced Treg accumulation and impaired Treg function in mouse models of cancer and autoimmune disease. TFEB intrinsically regulates genes involved in Treg cell differentiation and mitochondria function while it suppresses expression of proinflammatory cytokines independently of its established roles in autophagy. This coordinated action is required for mitochondria integrity and appropriate lipid metabolism in Treg cells. These findings identify TFEB as a critical regulator for orchestrating Treg generation and function, which may contribute to the adaptive responses of T cells to local environmental cues.


Assuntos
Adaptação Fisiológica , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Mitocôndrias , Neoplasias , Linfócitos T Reguladores , Adaptação Fisiológica/genética , Adaptação Fisiológica/fisiologia , Animais , Doenças Autoimunes/imunologia , Autofagia/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/fisiologia , Modelos Animais de Doenças , Interleucina-2/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Front Immunol ; 13: 899068, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35795660

RESUMO

Immunotherapies targeting the "don't eat me" myeloid checkpoint constituted by CD47 SIRPα interaction have promising clinical potential but are limited by toxicities associated with the destruction of non-tumor cells. These dose-limiting toxicities demonstrate the need to highlight the mechanisms of anti-CD47-SIRPα therapy effects on non-tumor CD47-bearing cells. Given the increased incidence of lymphopenia in patients receiving anti-CD47 antibodies and the strong ADCC (antibody-dependent cellular cytotoxicity) effector function of polymorphonuclear cells (PMNs), we investigated the behavior of primary PMNs cocultured with primary T cells in the presence of anti-CD47 mAbs. PMNs killed T cells in a CD47-mAb-dependent manner and at a remarkably potent PMN to T cell ratio of 1:1. The observed cytotoxicity was produced by a novel combination of both trogocytosis and a strong respiratory burst induced by classical ADCC and CD47-SIRPα checkpoint blockade. The complex effect of the CD47 blocking mAb could be recapitulated by combining its individual mechanistic elements: ADCC, SIRPα blockade, and ROS induction. Although previous studies had concluded that disruption of SIRPα signaling in PMNs was limited to trogocytosis-specific cytotoxicity, our results suggest that SIRPα also tightly controls activation of NADPH oxidase, a function demonstrated during differentiation of immature PMNs but not so far in mature PMNs. Together, our results highlight the need to integrate PMNs in the development of molecules targeting the CD47-SIRPα immune checkpoint and to design agents able to enhance myeloid cell function while limiting adverse effects on healthy cells able to participate in the anti-tumor immune response.


Assuntos
Antígenos de Diferenciação , Antígeno CD47 , NADPH Oxidases , Neoplasias , Receptores Imunológicos , Linfócitos T , Trogocitose , Anticorpos Monoclonais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos , Antígenos de Diferenciação/imunologia , Antígeno CD47/imunologia , Ativação Enzimática , Humanos , Contagem de Linfócitos , NADPH Oxidases/imunologia , NADPH Oxidases/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Receptores Imunológicos/imunologia , Linfócitos T/imunologia , Trogocitose/imunologia
8.
Proc Natl Acad Sci U S A ; 119(29): e2119736119, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858315

RESUMO

In the current era of T cell-based immunotherapies, it is crucial to understand which types of MHC-presented T cell antigens are produced by tumor cells. In addition to linear peptide antigens, chimeric peptides are generated through proteasome-catalyzed peptide splicing (PCPS). Whether such spliced peptides are abundantly presented by MHC is highly disputed because of disagreement in computational analyses of mass spectrometry data of MHC-eluted peptides. Moreover, such mass spectrometric analyses cannot elucidate how much spliced peptides contribute to the pool of immunogenic antigens. In this Perspective, we explain the significance of knowing the contribution of spliced peptides for accurate analyses of peptidomes on one hand, and to serve as a potential source of targetable tumor antigens on the other hand. Toward a strategy for mass spectrometry independent estimation of the contribution of PCPS to the immunopeptidome, we first reviewed methodologies to identify MHC-presented spliced peptide antigens expressed by tumors. Data from these identifications allowed us to compile three independent datasets containing 103, 74, and 83 confirmed T cell antigens from cancer patients. Only 3.9%, 1.4%, and between 0% and 7.2% of these truly immunogenic antigens are produced by PCPS, therefore providing a marginal contribution to the pool of immunogenic tumor antigens. We conclude that spliced peptides will not serve as a comprehensive source to expand the number of targetable antigens for immunotherapies.


Assuntos
Antígenos de Neoplasias , Antígenos de Histocompatibilidade Classe I , Neoplasias , Complexo de Endopeptidases do Proteassoma , Processamento de Proteína , Linfócitos T , Apresentação de Antígeno , Antígenos de Neoplasias/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Neoplasias/imunologia , Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Linfócitos T/imunologia
9.
FEBS Lett ; 596(16): 1981-1993, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35899372

RESUMO

Nuclear factor erythroid-derived 2-like 2 (NRF2) is a master transcription factor that coordinately regulates the expression of many cytoprotective genes and plays a central role in defense mechanisms against oxidative and electrophilic insults. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental. Many human cancers exhibit persistent NRF2 activation and such cancer cells rely on NRF2 for most of their malignant characteristics, such as therapeutic resistance and aggressive tumourigenesis, and thus fall into NRF2 addiction. The persistent activation of NRF2 confers great advantages on cancer cells, whereas it is not tolerated by normal cells, suggesting that certain requirements are necessary for a cell to exploit NRF2 and evolve into malignant cancer cells. In this review, recent reports and data on the genetic, metabolic and immunological features of NRF2-activated cancer cells are summarized, and prerequisites for NRF2 addiction in cancer cells and their therapeutic applications are discussed.


Assuntos
Fator 2 Relacionado a NF-E2 , Neoplasias , Carcinogênese , Regulação da Expressão Gênica , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Oxirredução , Estresse Oxidativo
10.
Front Immunol ; 13: 947568, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865518

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a member of the Janus kinase (JAK)-STAT pathway, which is one of the key pathways contributing to cancer. STAT3 regulates transcription downstream of many cytokines including interleukin (IL)-6 and IL-10. In cancer, STAT3 is mainly described as a tumor promoter driving tumor cell proliferation, resistance to apoptosis, angiogenesis and metastasis and aberrant activation of STAT3 is associated with poor prognosis. STAT3 is also an important driver of immune evasion. Among many other immunosuppressive mechanisms, STAT3 aids tumor cells to escape natural killer (NK) cell-mediated immune surveillance. NK cells are innate lymphocytes, which can directly kill malignant cells but also regulate adaptive immune responses and contribute to the composition of the tumor microenvironment. The inborn ability to lyse transformed cells renders NK cells an attractive tool for cancer immunotherapy. Here, we provide an overview of the role of STAT3 in the dynamic interplay between NK cells and tumor cells. On the one hand, we summarize the current knowledge on how tumor cell-intrinsic STAT3 drives the evasion from NK cells. On the other hand, we describe the multiple functions of STAT3 in regulating NK-cell cytotoxicity, cytokine production and their anti-tumor responses in vivo. In light of the ongoing research on STAT3 inhibitors, we also discuss how targeting STAT3 would affect the two arms of STAT3-dependent regulation of NK cell-mediated anti-tumor immunity. Understanding the complexity of this interplay in the tumor microenvironment is crucial for future implementation of NK cell-based immunotherapies.


Assuntos
Células Matadoras Naturais , Neoplasias , Fator de Transcrição STAT3 , Citocinas/metabolismo , Humanos , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral
11.
Front Immunol ; 13: 870726, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774795

RESUMO

Background: Inappropriate repair of DNA damage drives carcinogenesis. Lymphoid-specific helicase (HELLS) is an important component of the chromatin remodeling complex that helps repair DNA through various mechanisms such as DNA methylation, histone posttranslational modification, and nucleosome remodeling. Its role in human cancer initiation and progression has garnered recent attention. Our study aims to provide a more systematic and comprehensive understanding of the role of HELLS in the development and progression of multiple malignancies through analysis of HELLS in cancers. Methods: We explored the role of HELLS in cancers using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Multiple web platforms and software were used for data analysis, including R, Cytoscape, HPA, Archs4, TISIDB, cBioPortal, STRING, GSCALite, and CancerSEA. Results: High HELLS expression was found in a variety of cancers and differentially expressed across molecular and immune subtypes. HELLS was involved in many cancer pathways. Its expression positively correlated with Th2 and Tcm cells in most cancers. It also correlated with genetic markers of immunomodulators in various cancers. Conclusions: Our study elucidates the role HELLS plays in promotion, inhibition, and treatment of different cancers. HELLS is a potential cancer diagnostic and prognostic biomarker with immune, targeted, or cytotoxic therapeutic value. This work is a prerequisite to clinical validation and treatment of HELLS in cancers.


Assuntos
DNA Helicases , Neoplasias , Biologia Computacional , DNA Helicases/genética , DNA Helicases/imunologia , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/imunologia , Nucleossomos/genética , Prognóstico
12.
Oncoimmunology ; 11(1): 2093054, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35800155

RESUMO

Inducing a full antitumor immune response in the tumor microenvironment (TME) is essential for successful cancer immunotherapy. Here, we report that an oncolytic adenovirus carrying mIL-15 (Ad-IL15) can effectively induce antitumor immune response and inhibit tumor growth in a mouse model of cancer. We found that Ad-IL15 facilitated the activation and infiltration of immune cells, including dendritic cells (DCs), T cells and natural killer (NK) cells, in the TME. Unexpectedly, we observed that Ad-IL15 also induced vascular normalization and tertiary lymphoid structure formation in the TME. Moreover, we demonstrated these Ad-IL15-induced changes in the TME were depended on the Ad-IL15-induced activation of the STING-TBK1-IRF3 pathway in DCs. Taken together, our findings suggest that Ad-IL15 is a candidate for cancer immunotherapy that promotes immune cell activation and infiltration, tumor vascular normalization and tertiary lymphoid structure formation in the TME.


Assuntos
Interleucina-15 , Proteínas de Membrana , Estruturas Linfoides Terciárias , Adenoviridae/genética , Adenoviridae/imunologia , Animais , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Imunoterapia , Interleucina-15/administração & dosagem , Interleucina-15/imunologia , Proteínas de Membrana/imunologia , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/virologia , Terapia Viral Oncolítica
13.
J Immunother Cancer ; 10(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35793866

RESUMO

BACKGROUND: Cell therapy has shown promise in the treatment of certain solid tumors, but its efficacy may be limited by inhibition of therapeutic T cells by the programmed cell death protein-1 (PD-1) receptor. Clinical trials are testing cell therapy in combination with PDCD1 disruption or PD-1-axis blockade. However, preclinical data to support these approaches and to guide the treatment design are lacking. METHODS: Mechanisms of tumor regression and interaction between cell therapy and PD-1 blockade were investigated in congenic murine tumor models based on targeting established, solid tumors with T-cell receptor T cells directed against tumor-restricted, non-self antigens (ie, tumor neoantigens). RESULTS: In solid tumor models of cell therapy, PD-1 blockade mediated a reproducible but non-synergistic increase in tumor regression following adoptive T-cell transfer. Tumor regression was associated with increased tumor infiltration by endogenous T cells but not by transferred T cells. The effect was independent of PD-1 receptor expression by transferred T cells and was dependent on the endogenous T-cell repertoire and on tumor antigenicity. PD-1 blockade primarily induced cell state changes in endogenous tumor-antigen-specific T cells rather than transferred T cells. CONCLUSIONS: Together, these findings support the concept that PD-1 blockade acts primarily through endogenous rather than transferred T cells to mediate a non-synergistic antitumor effect in solid tumor cell therapy. These findings have important implications for strategies to leverage PD-1 receptor disruption or blockade to enhance the efficacy of cell therapy.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Neoplasias , Receptor de Morte Celular Programada 1 , Animais , Antígenos de Neoplasias , Humanos , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/metabolismo
14.
Int J Mol Sci ; 23(14)2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35886918

RESUMO

STAT3 and KRAS regulate cell proliferation, survival, apoptosis, cell migration, and angiogenesis. Aberrant expression of STAT3 and mutant active forms of KRAS have been well-established in the induction and maintenance of multiple cancers. STAT3 and KRAS mutant proteins have been considered anti-cancer targets; however, they are also considered to be clinically "undruggable" intracellular molecules, except for KRAS(G12C). Here we report a first-in-class molecule, a novel, single domain camelid VHH antibody (15 kDa), SBT-100, that binds to both STAT3 and KRAS and can penetrate the tumor cell membrane, and significantly inhibit cancer cell growth. Additionally, SBT-100 inhibits KRAS GTPase activity and downstream phosphorylation of ERK in vitro. In addition, SBT-100 inhibits the growth of multiple human cancers in vitro and in vivo. These results demonstrate the feasibility of targeting hard-to-reach aberrant intracellular transcription factors and signaling proteins simultaneously with one VHH to improve cancer therapies.


Assuntos
Anticorpos Biespecíficos , Antineoplásicos Imunológicos , Anticorpos de Domínio Único , Anticorpos Biespecíficos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Mutação , Neoplasias/imunologia , Neoplasias/terapia , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator de Transcrição STAT3 , Anticorpos de Domínio Único/farmacologia
15.
Front Immunol ; 13: 878959, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35833131

RESUMO

Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.


Assuntos
Interferon Tipo I , Neoplasias , Receptor de Interferon alfa e beta , Animais , Interferon Tipo I/imunologia , Linfonodos , Camundongos , Neoplasias/imunologia , Neutrófilos/imunologia , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais , Microambiente Tumoral
16.
Front Immunol ; 13: 926714, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35874734

RESUMO

Exhausted CD8+ T (Tex) cells are a distinct cell population that arise during persistent antigen exposure in the context of chronic infections and cancers. Although characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression and distinct transcriptional and epigenetic programs, Tex cells are heterogeneous. Among these, a self-renewing TCF-1+ Tex population, having unique characteristics and the ability to respond to immune-checkpoint blockade, gives rise to TCF-1- terminally Tex cells. These TCF-1+ cells have stem cell-like properties similar to memory T cell populations, but the signals that regulate the developmental pathways and relationships among exhausted cell populations are still unclear. Here, we review our current understanding of Tex cell biology, and discuss some less appreciated molecules and pathways affecting T cell exhaustion. We highlight two co-stimulatory receptors, CD226 and CD137, and their role in inducing or restraining T cell exhaustion, as well as signaling pathways that may be amenable to pharmacological inhibition with a focus on Phosphoinositide-3 Kinase and IL-2 partial agonists. Finally, we discuss novel methods that may increase TCF-1+ populations and therefore improve immunotherapy responsiveness. Understanding features of and pathways to exhaustion has important implications for the success of immunotherapy, including checkpoint blockade and adoptive T-cell transfer therapies.


Assuntos
Linfócitos T CD8-Positivos , Imunoterapia , Humanos , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia
17.
Gene ; 840: 146765, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35905855

RESUMO

BACKGROUND: BRCA1-associated protein 1 gene (BAP1) plays a key role in some cancers. However, it has not yet been elucidated whether BAP1 modulates the pathogenesis and progression of human cancers through some common cellular and molecular mechanisms, and a pan-cancer analysis for the roles of BAP1 has not yet been conducted. METHODS: A systematic assessment of the BAP1 gene was presented using bioinformatics analysis and R software. Based on gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, differential expression of BAP1, survival prognosis and genetic alterations of BAP1, correlations between BAP1 expression and immune infiltrates, enrichment analysis and receiver operating curves (ROC) were performed across 33 TCGA cancers. RESULTS: BAP1 was highly expressed in several cancers and high BAP1 expression resulted in different survival prognoses. BAP1 DNA methylation status was changed in uveal melanoma (UVM) cases and a high level of BAP1 phosphorylation was found at the S292 locus in several cancers (colon cancer, lung adenocarcinoma, breast cancer, ovarian cancer, and uterine cancer). The statistically significant correlations of BAP1 expression and immune infiltration may contribute to the prognostic survivals in several cancers including UVM, skin cutaneous melanoma (SKCM), and lung adenocarcinoma (LUAD). Additionally, the correlations between BAP1 expression and tumor mutation burden (TMB)/microsatellite instability (MSI) across TCGA cancers were also explored. Finally, the analysis revealed that BAP1 expression level had high sensitivity and specificity for liver hepatocellular carcinoma (LIHC), kidney renal clear cell carcinoma (KIRC), and pancreatic adenocarcinoma (PAAD) patients. CONCLUSION: This study has revealed statistically significant correlations of BAP1 expression with survival analysis, DNA methylation, protein phosphorylation, genetic alteration, and immune infiltration across multiple TCGA cancers, suggesting that BAP1 may potentially serve as a potential therapeutic target and prognostic biomarker for several cancers.


Assuntos
Neoplasias/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteína BRCA1/metabolismo , Humanos , Neoplasias/imunologia , Prognóstico , Ubiquitina Tiolesterase
18.
Front Immunol ; 13: 901273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844527

RESUMO

Background: Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients. Methods: A cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks. Results: Monocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density. Conclusions: Dampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.


Assuntos
Antígenos HLA-DR , Transplante de Rim , Monócitos , Células Supressoras Mieloides , Neoplasias , Estudos de Coortes , Citocinas/imunologia , Antígenos HLA-DR/imunologia , Humanos , Monócitos/imunologia , Monócitos/patologia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/patologia , Transplantados
19.
Nucleic Acids Res ; 50(14): 8093-8106, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35849338

RESUMO

DNA damage response pathways rely extensively on nuclease activity to process DNA intermediates. Exonuclease 1 (EXO1) is a pleiotropic evolutionary conserved DNA exonuclease involved in various DNA repair pathways, replication, antibody diversification, and meiosis. But, whether EXO1 facilitates these DNA metabolic processes through its enzymatic or scaffolding functions remains unclear. Here, we dissect the contribution of EXO1 enzymatic versus scaffolding activity by comparing Exo1DA/DA mice expressing a proven nuclease-dead mutant form of EXO1 to entirely EXO1-deficient Exo1-/- and EXO1 wild type Exo1+/+ mice. We show that Exo1DA/DA and Exo1-/- mice are compromised in canonical DNA repair processing, suggesting that the EXO1 enzymatic role is important for error-free DNA mismatch and double-strand break repair pathways. However, in non-canonical repair pathways, EXO1 appears to have a more nuanced function. Next-generation sequencing of heavy chain V region in B cells showed the mutation spectra of Exo1DA/DA mice to be intermediate between Exo1+/+ and Exo1-/- mice, suggesting that both catalytic and scaffolding roles of EXO1 are important for somatic hypermutation. Similarly, while overall class switch recombination in Exo1DA/DA and Exo1-/- mice was comparably defective, switch junction analysis suggests that EXO1 might fulfill an additional scaffolding function downstream of class switching. In contrast to Exo1-/- mice that are infertile, meiosis progressed normally in Exo1DA/DA and Exo1+/+ cohorts, indicating that a structural but not the nuclease function of EXO1 is critical for meiosis. However, both Exo1DA/DA and Exo1-/- mice displayed similar mortality and cancer predisposition profiles. Taken together, these data demonstrate that EXO1 has both scaffolding and enzymatic functions in distinct DNA repair processes and suggest a more composite and intricate role for EXO1 in DNA metabolic processes and disease.


Assuntos
Enzimas Reparadoras do DNA , Reparo do DNA , Exodesoxirribonucleases , Neoplasias , Animais , Linfócitos B , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Imunidade , Meiose/genética , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Hipermutação Somática de Imunoglobulina
20.
Cancer Immunol Res ; 10(8): 918, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35802596

RESUMO

In this issue of Cancer Immunology Research, Ferris and colleagues demonstrate that type 1 conventional DC (cDC1) vaccines drive tumor rejection through direct antigen presentation, without the need of endogenous cDC1. This suggests that cDC1-based vaccines could represent an optimal strategy to induce antitumor immunity in patients. See related article by Ferris et al., p. 920 (7) .


Assuntos
Vacinas Anticâncer , Neoplasias , Apresentação de Antígeno/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Humanos , Neoplasias/imunologia , Linfócitos T/imunologia
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