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1.
Nat Commun ; 12(1): 5024, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408137

RESUMO

There is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.


Assuntos
Neoplasias da Mama/imunologia , Mama/patologia , Evasão Tumoral , Animais , Mama/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Neutrófilos/imunologia , Análise de Célula Única
2.
FASEB J ; 35(9): e21750, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34424568

RESUMO

Success of adoptive cell therapy mainly depends on the ability of immune cells to persist and function optimally in the immunosuppressive tumor microenvironment. Although present at the cancer site, immune cells become exhausted and/or inhibited, due to the presence of inhibitory receptors such as PD-L1 on malignant cells. Novel genetic strategies to manipulate the PD1/PD-L1 axis comprise (i) PD-1 reversion where the receptor intracellular domain is replaced with an activating unit, (ii) the use of anti-PD-L1 CAR or (iii) the disruption of the PD-1 gene. We here present an alternative strategy to equip therapeutic cells with a truncated PD-1 (tPD-1) to abrogate PD-1/PD-L1 inhibition. We show that engagement of tPD-1 with PD-L1-positive tumor unleashes NK-92 activity in vitro. Furthermore, this binding was sufficiently strong to induce killing of targets otherwise not recognized by NK-92, thus increasing the range of targets. In vivo treatment with NK-92 tPD-1 cells led to reduced tumor growth and improved survival. Importantly, tPD-1 did not interfere with tumor recognition in PD-L1 negative conditions. Thus, tPD-1 represents a straightforward method for improving antitumor immunity and revealing new targets through PD-L1 positivity.


Assuntos
Antígeno B7-H1/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Evasão Tumoral/imunologia , Animais , Adesão Celular , Engenharia Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Engenharia Genética , Humanos , Camundongos , Neoplasias/patologia , Receptor de Morte Celular Programada 1/metabolismo , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201655

RESUMO

It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.


Assuntos
Antígenos de Neoplasias/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias/terapia , Evasão Tumoral/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Regulação para Baixo , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Mutação , Neoplasias/imunologia
4.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206399

RESUMO

Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy.


Assuntos
Suscetibilidade a Doenças , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Biomarcadores , Comunicação Celular , Gerenciamento Clínico , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Ligantes , Ligação Proteica , Receptores de Células Matadoras Naturais/genética , Receptores de Células Matadoras Naturais/metabolismo , Resultado do Tratamento , Evasão Tumoral/genética , Evasão Tumoral/imunologia
5.
Nat Commun ; 12(1): 4193, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234122

RESUMO

Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.


Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/imunologia , Neoplasias Nasofaríngeas/imunologia , Evasão Tumoral/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Viral da Expressão Gênica/imunologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/metabolismo , Camundongos , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virologia , Nasofaringe/imunologia , Nasofaringe/patologia , Nasofaringe/cirurgia , Nasofaringe/virologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Deleção de Sequência , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Evasão Tumoral/efeitos dos fármacos , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298868

RESUMO

Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignancy. They also may contribute to the search of new targets for cancer treatment, such as FAP-expressing cancer-associated fibroblasts, in refractory bladder tumors.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Citotóxicos/imunologia , Evasão Tumoral/imunologia , Neoplasias da Bexiga Urinária/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Fenótipo , Microambiente Tumoral/imunologia , Adulto Jovem
7.
Front Immunol ; 12: 624725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084160

RESUMO

MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.


Assuntos
MicroRNAs/imunologia , Neoplasias/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , Animais , Antineoplásicos/uso terapêutico , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Progressão da Doença , Humanos , Imunoterapia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Fenótipo , Evasão Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo
8.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066087

RESUMO

Immune evasion is a key strategy adopted by tumor cells to escape the immune system while promoting their survival and metastatic spreading. Indeed, several mechanisms have been developed by tumors to inhibit immune responses. PD-1 is a cell surface inhibitory receptor, which plays a major physiological role in the maintenance of peripheral tolerance. In pathological conditions, activation of the PD-1/PD-Ls signaling pathway may block immune cell activation, a mechanism exploited by tumor cells to evade the antitumor immune control. Targeting the PD-1/PD-L1 axis has represented a major breakthrough in cancer treatment. Indeed, the success of PD-1 blockade immunotherapies represents an unprecedented success in the treatment of different cancer types. To improve the therapeutic efficacy, a deeper understanding of the mechanisms regulating PD-1 expression and signaling in the tumor context is required. We provide an overview of the current knowledge of PD-1 expression on both tumor-infiltrating T and NK cells, summarizing the recent evidence on the stimuli regulating its expression. We also highlight perspectives and limitations of the role of PD-L1 expression as a predictive marker, discuss well-established and novel potential approaches to improve patient selection and clinical outcome and summarize current indications for anti-PD1/PD-L1 immunotherapy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Humanos , Neoplasias/fisiopatologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Evasão Tumoral
9.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072260

RESUMO

The understanding of the tumor microenvironment (TME) has been expanding in recent years in the context of interactions among different cell types, through direct cell-cell communication as well as through soluble factors. It has become evident that the development of a successful antitumor response depends on several TME factors. In this context, the number, type, and subsets of immune cells, as well as the functionality, memory, and exhaustion state of leukocytes are key factors of the TME. Both the presence and functionality of immune cells, in particular T cells, are regulated by cellular and soluble factors of the TME. In this regard, one fundamental reason for failure of antitumor responses is hijacked immune cells, which contribute to the immunosuppressive TME in multiple ways. Specifically, reactive oxygen species (ROS), metabolites, and anti-inflammatory cytokines have central roles in generating an immunosuppressive TME. In this review, we focused on recent developments in the immune cell constituents of the TME, and the micromilieu control of antitumor responses. Furthermore, we highlighted the current challenges of T cell-based immunotherapies and potential future strategies to consider for strengthening their effectiveness.


Assuntos
Imunomodulação , Neoplasias/imunologia , Neoplasias/patologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Biomarcadores , Humanos , Vigilância Imunológica , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Neoplasias/metabolismo , Neoplasias/terapia , Infiltração de Neutrófilos , Espécies Reativas de Oxigênio , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Linfócitos T/metabolismo , Resultado do Tratamento , Evasão Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
10.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070750

RESUMO

The immune system is a fine modulator of the tumor biology supporting or inhibiting its progression, growth, invasion and conveys the pharmacological treatment effect. Tumors, on their side, have developed escaping mechanisms from the immune system action ranging from the direct secretion of biochemical signals to an indirect reaction, in which the cellular actors of the tumor microenvironment (TME) collaborate to mechanically condition the extracellular matrix (ECM) making it inhospitable to immune cells. TME is composed of several cell lines besides cancer cells, including tumor-associated macrophages, cancer-associated fibroblasts, CD4+ and CD8+ lymphocytes, and innate immunity cells. These populations interface with each other to prepare a conservative response, capable of evading the defense mechanisms implemented by the host's immune system. The presence or absence, in particular, of cytotoxic CD8+ cells in the vicinity of the main tumor mass, is able to predict, respectively, the success or failure of drug therapy. Among various mechanisms of immunescaping, in this study, we characterized the modulation of the phenotypic profile of CD4+ and CD8+ cells in resting and activated states, in response to the mechanical pressure exerted by a three-dimensional in vitro system, able to recapitulate the rheological and stiffness properties of the tumor ECM.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Matriz Extracelular/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Cultura de Células , Módulo de Elasticidade , Matriz Extracelular/química , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Hidrogéis/química , Interferon gama/genética , Interferon gama/imunologia , Ativação Linfocitária , Mecanotransdução Celular , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Reologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologia
11.
Nat Immunol ; 22(7): 865-879, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140678

RESUMO

Reduced infiltration of anti-tumor lymphocytes remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that upregulation of regulator of G protein signaling (RGS)1 in helper TH1 cells and cytotoxic T lymphocytes (CTLs) reduced their trafficking to and survival in tumors and was associated with shorter survival of patients with breast and lung cancer. RGS1 was upregulated by type II interferon (IFN)-signal transducer and activator of transcription (STAT)1 signaling and impaired trafficking of circulating T cells to tumors by inhibiting calcium influx and suppressing activation of the kinases ERK and AKT. RGS1 knockdown in adoptively transferred tumor-specific CTLs significantly increased their infiltration and survival in breast and lung tumor grafts and effectively inhibited tumor growth in vivo, which was further improved when combined with programmed death ligand (PD-L)1 checkpoint inhibition. Our findings reveal RGS1 is important for tumor immune evasion and suggest that targeting RGS1 may provide a new strategy for tumor immunotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Quimiotaxia de Leucócito , Linfócitos do Interstício Tumoral/metabolismo , Proteínas RGS/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Técnicas de Cocultura , Citotoxicidade Imunológica , Feminino , Humanos , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/transplante , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Microscopia de Vídeo , Proteínas RGS/genética , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Fatores de Tempo , Imagem com Lapso de Tempo , Células Tumorais Cultivadas , Evasão Tumoral
12.
13.
Nat Commun ; 12(1): 2722, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976164

RESUMO

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.


Assuntos
Adenocarcinoma in Situ/genética , Adenocarcinoma de Pulmão/genética , Carcinogênese/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Lesões Pré-Cancerosas/genética , Transcriptoma , Adenocarcinoma in Situ/imunologia , Adenocarcinoma in Situ/patologia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Carcinogênese/imunologia , Carcinogênese/patologia , Aberrações Cromossômicas , Células Clonais , Variações do Número de Cópias de DNA , Metilação de DNA , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/imunologia , Lesões Pré-Cancerosas/imunologia , Lesões Pré-Cancerosas/patologia , Transdução de Sinais , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
14.
Theranostics ; 11(13): 6427-6444, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995666

RESUMO

Background: Reportedly, nasopharyngeal carcinoma (NPC) patients with MHC I Class aberration are prone to poor survival outcomes, which indicates that the deficiency of tumor neoantigens might represent a mechanism of immune surveillance escape in NPC. Methods: To clearly delineate the landscape of neoantigens in NPC, we performed DNA and RNA sequencing on paired primary tumor, regional lymph node metastasis and distant metastasis samples from 26 patients. Neoantigens were predicted using pVACseq pipeline. Subtype prediction model was built using random forest algorithm. Results: Portraying the landscape of neoantigens in NPC for the first time, we found that the neoantigen load of NPC was above average compared to that of other cancers in The Cancer Genome Atlas program. While the quantity and quality of neoantigens were similar among primary tumor, regional lymph node metastasis and distant metastasis samples, neoantigen depletion was more severe in metastatic sites than in primary tumors. Upon tracking the clonality change of neoantigens, we found that neoantigen reduction occurred during metastasis. Building a subtype prediction model based on reported data, we observed that subtype I lacked T cells and suffered from severe neoantigen depletion, subtype II highly expressed immune checkpoint molecules and suffered from the least neoantigen depletion, and subtype III was heterogenous. Conclusions: These results indicate that neoantigens are conducive to the guidance of clinical treatment, and personalized therapeutic vaccines for NPC deserve deeper basic and clinical investigations to make them feasible in the future.


Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/imunologia , Adulto , Antígenos de Neoplasias/genética , DNA de Neoplasias/genética , DNA Viral/análise , DNA Viral/genética , Feminino , Antígenos HLA/genética , Antígenos HLA/imunologia , Herpesvirus Humano 4/genética , Humanos , Mutação INDEL , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Metástase Linfática/imunologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virologia , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , RNA Neoplásico/genética , Receptores de Antígenos de Linfócitos T/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , Infecções Tumorais por Vírus/virologia
15.
Aging (Albany NY) ; 13(9): 12691-12709, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33973529

RESUMO

Due to its effectiveness, cancer immunotherapy has attracted widespread attention from clinicians and scientific researchers. Numerous studies have proven that effective stratification of cancer patients would promote the personalized application of immunotherapy. Therefore, we used the transcriptome data of nearly 1,000 patients with non-small cell lung cancer (NSCLC) to construct a new immune subgroup. We found that the new immune subgroup, named cluster 2, was a mixture of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and showed poor overall survival, which was further verified in the independent validation set. Immune infiltration correlation analysis showed that the Mast cell type and its status subdivisions had a predictive effect on the prognosis of NSCLC, especially in LUAD. Phenotypic analysis suggested that epithelial-mesenchymal transition (EMT) was positively correlated with immunosuppression, supporting the correlation between tumor phenotype and immune background. Although immune subtypes failed to significantly distinguish the progression-free survival (PFS) of immunotherapy patients, they showed the expected trend; the sample size needs to be further expanded for verification. In addition, some results indicated that the two cancer types, LUAD and LUSC, might require independent analyses.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/mortalidade , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Mastócitos/imunologia , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , RNA-Seq , Transcriptoma/imunologia , Evasão Tumoral/genética
16.
Cancer Sci ; 112(7): 2705-2713, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34009705

RESUMO

Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden "stealth" antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re-expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re-expression in xenografts in BALB/c-nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T-cells with a SPESP1-derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1-specific helper T-cells were obtained; these cells produced interferon-γ against HLA-matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.


Assuntos
Antígenos de Neoplasias/imunologia , Proteínas de Transporte/imunologia , Epigênese Genética/imunologia , Neoplasias/imunologia , Proteínas de Plasma Seminal/imunologia , Animais , Antígenos de Neoplasias/genética , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Epigênese Genética/efeitos dos fármacos , Epitopos de Linfócito T/imunologia , Humanos , Imunoterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/genética , Neoplasias/terapia , Proteínas de Plasma Seminal/genética , Linfócitos T Auxiliares-Indutores/imunologia , Evasão Tumoral/genética
17.
Am J Pathol ; 191(8): 1353-1363, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34043978

RESUMO

Breast cancer (BC) accounts for significant morbidity and mortality among women worldwide. About one in three patients with breast cancer present with lymph node (LN) metastasis and LN status is one of the most important prognostic predictors in patients with BC. In addition to their prognostic value, LNs initiate adaptive immunity against BC. Yet, BC cells often avoid immune-mediated destruction in LNs. This review provides an overview of the ways by which BC cells modulate LN stromal and hematopoietic cells to promote metastasis and immune evasion.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Metástase Linfática/imunologia , Metástase Linfática/patologia , Evasão Tumoral/imunologia , Feminino , Humanos
18.
Clin Exp Metastasis ; 38(3): 279-293, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34014424

RESUMO

Metastasis is the primary cause of cancer mortality and an improved understanding of its pathology is critical to the development of novel therapeutic approaches. Mechanism-based therapeutic strategies require insight into the timing of tumor cell dissemination, seeding of distant organs, formation of occult lesions and critically, their release from dormancy. Due to imaging limitations, primary tumors can only be detected when they reach a relatively large size (e.g. > 1 cm3), which, based on our understanding of tumor evolution, occurs approximately 10 years and about 30 doubling times following tumor initiation. Genomic profiling of paired primary tumors and metastases has suggested that tumor seeding at secondary sites occurs early during tumor progression and frequently, years prior to clinical diagnosis. Following seeding, tumor cells may enter into and remain in a dormant state, and if they survive and are released from dormancy, they can proliferate into an overt lesion. The timeline of tumor initiation and metastatic dormancy is regulated by tumor interactions with its microenvironment, angiogenesis, and tumor-specific cytotoxic T-lymphocyte (CTL) responses. Therefore, a better understanding of the cellular interactions responsible for immune evasion and/or tumor cell release from dormancy would facilitate the development of therapeutics targeted against this critical part of tumor progression. The immunosuppressive mechanisms mediated by myeloid-derived suppressor cells (MDSCs) contribute to tumor progression and, we posit, promote tumor cell escape from CTL-associated dormancy. Thus, while clinical and translational research has demonstrated a role for MDSCs in facilitating tumor progression and metastasis through tumor escape from adoptive and innate immune responses (T-, natural killer and B-cell responses), few studies have considered the role of MDSCs in tumor release from dormancy. In this review, we discuss MDSC expansion, driven by tumor burden associated growth factor secretion and their role in tumor cell escape from dormancy, resulting in manifest metastases. Thus, the therapeutic strategies to inhibit MDSC expansion and function may provide an approach to delay metastatic relapse and prolong the survival of patients with advanced malignancies.


Assuntos
Células Supressoras Mieloides/imunologia , Micrometástase de Neoplasia/patologia , Neoplasias/patologia , Evasão Tumoral/imunologia , Animais , Humanos , Micrometástase de Neoplasia/imunologia , Neoplasias/imunologia
19.
Nat Commun ; 12(1): 2815, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990566

RESUMO

Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding escape from antitumor immunity and optimizing T cell-related therapeutic strategies. Here, we engineered nanotextured elastic platforms to study and enhance T cell migration through complex microenvironments and define how the balance between contractility localization-dependent T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues. Using these platforms, we characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubule instability, leading to increased Rho pathway-dependent cortical contractility, promotes migration whereas clinically used microtubule-stabilizing chemotherapies profoundly decrease effective migration. We show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and interrogate 3D matrix and tumor volumes. Thus, engineering cells to better navigate through 3D microenvironments could be part of an effective strategy to enhance efficacy of immune therapeutics.


Assuntos
Movimento Celular/fisiologia , Linfócitos T/imunologia , Linfócitos T/fisiologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/fisiologia , Animais , Fenômenos Biomecânicos , Células Cultivadas , Matriz Extracelular/imunologia , Matriz Extracelular/fisiologia , Técnicas de Inativação de Genes , Engenharia Genética , Humanos , Camundongos , Camundongos Transgênicos , Microtúbulos/fisiologia , Modelos Biológicos , Nanoestruturas , Fatores de Troca de Nucleotídeo Guanina Rho/antagonistas & inibidores , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Troca de Nucleotídeo Guanina Rho/fisiologia , Evasão Tumoral/imunologia , Evasão Tumoral/fisiologia
20.
Nat Commun ; 12(1): 3236, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050151

RESUMO

Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptor A2A de Adenosina/genética , Linfócitos T/transplante , Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Sistemas CRISPR-Cas/genética , Engenharia Celular/métodos , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Edição de Genes , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/imunologia , RNA Interferente Pequeno/metabolismo , RNA-Seq , Receptor A2A de Adenosina/metabolismo , Receptor ErbB-2/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/genética
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