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1.
Anticancer Res ; 41(9): 4515-4522, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475077

RESUMO

BACKGROUND/AIM: The role of tumour-infiltrating CD45Ro+ T-cells in oral squamous cell carcinoma (OSCC) is unclear. This study aimed to evaluate prognostic biomarkers for OSCC. PATIENTS AND METHODS: We determined the density of tumour-infiltrating CD45Ro+ T cells in the parenchyma and stroma at the tumour centre (TCe) and invasive front (IF) and examined the association between the density of these cells and histopathological status in 142 patients. RESULTS: Five-year overall survival (OS) and recurrence-free survival were favourable in patients with high CD45Ro+ T-cell density in the TCe stroma. OS was favourable in patients with high CD45Ro+ T-cell density in the IF stroma. Stepwise Cox regression model analysis indicated that CD45Ro+ T-cells in the stroma of the IF and TCe were an independent prognostic factor for OS. CONCLUSION: CD45Ro+ T-cells in the stroma of the IF and TCe play a role in cancer immune surveillance and may be a useful prognostic factor.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Antígenos Comuns de Leucócito/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Bucais/mortalidade , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/imunologia , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Análise de Sobrevida
2.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445631

RESUMO

To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.


Assuntos
Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Neoplasias Inflamatórias Mamárias/patologia , Linfócitos do Interstício Tumoral/imunologia , Terapia de Alvo Molecular , Mutação , Microambiente Tumoral/imunologia , Adulto , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Ácidos Nucleicos Livres/análise , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/imunologia , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
3.
J Immunol ; 207(5): 1468-1477, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34408009

RESUMO

Immuno-positron emission tomography (PET), a noninvasive imaging modality, can provide a dynamic approach for longitudinal assessment of cell populations of interest. Transformation of mAbs into single-chain variable fragment (scFv)-based PET imaging agents would allow noninvasive tracking in vivo of a wide range of possible targets. We used sortase-mediated enzymatic labeling in combination with PEGylation to develop an anti-mouse CD4 scFv-based PET imaging agent constructed from an anti-mouse CD4 mAb. This anti-CD4 scFv can monitor the in vivo distribution of CD4+ T cells by immuno-PET. We tracked CD4+ and CD8+ T cells in wild-type mice, in immunodeficient recipients reconstituted with monoclonal populations of OT-II and OT-I T cells, and in a B16 melanoma model. Anti-CD4 and -CD8 immuno-PET showed that the persistence of both CD4+ and CD8+ T cells transferred into immunodeficient mice improved when recipients were immunized with OVA in CFA. In tumor-bearing animals, infiltration of both CD4+ and CD8+ T cells increased as the tumor grew. The approach described in this study should be readily applicable to convert clinically useful Abs into the corresponding scFv PET imaging agents.


Assuntos
Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Monitorização Imunológica/métodos , Neoplasias Cutâneas/terapia , Animais , Anticorpos Monoclonais/metabolismo , Diagnóstico por Imagem , Feminino , Memória Imunológica , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tomografia por Emissão de Pósitrons , Anticorpos de Cadeia Única/metabolismo
4.
Front Immunol ; 12: 599207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267742

RESUMO

Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, numerous cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, serves as an alternative inhibitory receptor to be targeted in the clinic. The impacts of LAG3 on immune cell populations and coregulation of immune responses in breast cancer remain largely unknown. To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from 2,994 breast cancer patients. We estimated the landscape of the relationship between LAG3 and 10 types of cell populations of breast cancer. We investigated the correlation pattern between LAG3 and immune modulators in pancancer, particularly the synergistic role of LAG3 with other immune checkpoint members in breast cancer. LAG3 expression was closely related to the malignancy of breast cancer and may serve as a potential biomarker. LAG3 may play an important role in regulating the tumor immune microenvironment of T cells and other immune cells. More important, LAG3 may synergize with CTLA4, PD1/PDL1, and other immune checkpoints, thereby contributing more evidence to improve combination cancer immunotherapy by simultaneously targeting LAG3, PD1/PDL1, and CTLA4.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Expressão Gênica , Antígenos CD/imunologia , Neoplasias da Mama/classificação , Neoplasias da Mama/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Transcriptoma , Microambiente Tumoral/imunologia
5.
Anticancer Res ; 41(8): 3989-3995, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281863

RESUMO

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is one of the most lethal tumors. Given the failure of conventional therapeutic strategies, immunotherapy has emerged as a promising treatment modality that may improve the survival of patients with operable and advanced disease. PATIENTS AND METHODS: We examined the relative presence of CD20+ B-cells, CD8+ cytotoxic, and CD4+ helper/regulatory T-cells in the tumor-infiltrating lymphocyte (TIL)-population in a series of surgically-treated NSCLCs, and assessed their role as prognostic indicators after surgery. RESULTS: A high percent of CD4+ and CD8+ TILs in the tumor stroma was linked with poor (p=0.003) and good prognosis (p=0.01), respectively. High CD4/CD8 ratio defined a significantly worst prognosis [median survival 22 months vs. undefined, p=0.0002, hazard ratio (HR) 0.3 vs. 3.0]. Statistically significant results were also noted when the analysis was focused on the invading tumor front. In a multivariate model, the CD4/CD8-ratio assessed in the tumor stroma and the stage of disease were independent prognostic variables (p=0.0001, HR=4.1 and p=0.001, HR=1.5, respectively). CONCLUSION: The balance between CD4+ and CD8+ lymphocytes infiltrating the tumor stroma is a crucial factor defining anti-tumor immune surveillance, has strong prognostic value, and may be tested as a predictive biomarker for immunotherapy in operable NSCLC.


Assuntos
Antígenos CD20/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Nature ; 596(7870): 119-125, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290406

RESUMO

Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses1-3; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8+ T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide-human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma/imunologia , Especificidade por Substrato/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/sangue , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única , Transcriptoma/genética , Microambiente Tumoral
7.
Nature ; 596(7870): 126-132, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290408

RESUMO

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.


Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Cultivadas , Humanos , Memória Imunológica , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA-Seq , Receptores de Interleucina-7/imunologia , Análise de Célula Única , Transcriptoma/genética , Microambiente Tumoral
8.
Front Immunol ; 12: 557994, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220791

RESUMO

The immunosuppressive mechanisms of the surrounding microenvironment and distinct immunogenomic features in glioblastoma (GBM) have not been elucidated to date. To fill this gap, useful data were extracted from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GSE16011, GSE43378, GSE23806, and GSE12907. With the ssGSEA method and the ESTIMATE and CIBERSORT algorithms, four microenvironmental signatures were used to identify glioma microenvironment genes, and the samples were reasonably classified into three immune phenotypes. The molecular and clinical features of these phenotypes were characterized via key gene set expression, tumor mutation burden, fraction of immune cell infiltration, and functional enrichment. Exhausted CD8+ T cell (GET) signature construction with the predictive response to commonly used antitumor drugs and peritumoral edema assisted in further characterizing the immune phenotype features. A total of 2,466 glioma samples with gene expression profiles were enrolled. Tumor purity, ESTIMATE, and immune and stromal scores served as the 4 microenvironment signatures used to classify gliomas into immune-high, immune-middle and immune-low groups, which had distinct immune heterogeneity and clinicopathological characteristics. The immune-H phenotype had higher expression of four immune signatures; however, most checkpoint molecules exhibited poor survival. Enriched pathways among the subtypes were related to immunity. The GET score was similar among the three phenotypes, while immune-L was more sensitive to bortezomib, cisplatin, docetaxel, lapatinib, and rapamycin prescriptions and displayed mild peritumor edema. The three novel immune phenotypes with distinct immunogenetic features could have utility for understanding glioma microenvironment regulation and determining prognosis. These results contribute to classifying glioma subtypes, remodeling the immunosuppressive microenvironment and informing novel cancer immunotherapy in the era of precision immuno-oncology.


Assuntos
Neoplasias Encefálicas/genética , Linfócitos T CD8-Positivos/imunologia , Glioblastoma/genética , Glioma/genética , Linfócitos do Interstício Tumoral/imunologia , Algoritmos , Antineoplásicos , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Edema , Regulação Neoplásica da Expressão Gênica , Genoma , Glioblastoma/diagnóstico , Glioblastoma/mortalidade , Glioma/diagnóstico , Glioma/mortalidade , Humanos , Imunogenética/métodos , Imunofenotipagem , Prognóstico , Análise de Sobrevida , Transcriptoma , Microambiente Tumoral/genética
9.
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
10.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299016

RESUMO

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial-mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Carcinoma/imunologia , Carcinoma/metabolismo , Transição Epitelial-Mesenquimal/imunologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
11.
Commun Biol ; 4(1): 859, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253827

RESUMO

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells.


Assuntos
Linfócitos B/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/terapia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Chlorocebus aethiops , Terapia Combinada , Feminino , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Terapia Viral Oncolítica/métodos , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Células Vero
12.
Nat Immunol ; 22(8): 983-995, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34282330

RESUMO

The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos-Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8+ T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF-IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD8-Positivos/imunologia , Fatores Reguladores de Interferon/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Transcrição NFATC/metabolismo , Recidiva Local de Neoplasia/imunologia , Fator de Transcrição AP-1/metabolismo
13.
Aging (Albany NY) ; 13(12): 16287-16315, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34230220

RESUMO

N6-methyladenosine (m6A) RNA methylation is associated with malignant tumor progression and is modulated by various m6A RNA methylation regulator proteins. However, its role in endometrial cancer is unclear. In this work, we analyzed sequence, copy number variation, and clinical data obtained from the TCGA database. Expression was validated using real-time quantitative polymerase chain reaction and immunohistochemistry. Changes in m6A RNA methylation regulators were closely related to the clinicopathological stage and prognosis of endometrial cancer. In particular, ZC3H13, YTHDC1, and METTL14 were identified as potential markers for endometrial cancer diagnosis and prognosis. The TIMER algorithm indicated that immune cell infiltration correlated with changes in ZC3H13, YTHDC1, and METTL14 expression. Meanwhile, ZC3H13 or YTHDC1 knockdown promoted the proliferation and invasion of endometrial cancer cells. Through gene enrichment analysis, we constructed a regulatory network in order to explore the potential molecular mechanism involving ZC3H13, YTHDC1, and METTL14. Virtual screening predicted interactions of potential therapeutic compounds with METTL14 and YTHDC1. These findings advance the understanding of RNA epigenetic modifications in endometrial cancer while identifying m6A regulators associated with immune infiltration, prognosis, and potential treatment strategies.


Assuntos
Adenosina/análogos & derivados , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Linfócitos do Interstício Tumoral/imunologia , Adenosina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Variações do Número de Cópias de DNA/genética , Intervalo Livre de Doença , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Ligantes , Metilação , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Mutação/genética , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Microambiente Tumoral/imunologia
14.
J Egypt Natl Canc Inst ; 33(1): 16, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34241710

RESUMO

BACKGROUND: P D-L1 is expressed in tumor cells and plays a crucial role in tumor immune escape. Tumor-infiltrating lymphocytes (TILs) as CD8 T cells contribute to reduced tumor growth. Few studies investigated the prognostic effect of PD-L1 and CD8 TILs in ovarian high-grade serous carcinoma (HGSC). In the present study, we analyzed the expression of PD-L1 and CD8 TILs in HGSC by immunohistochemistry, and results were correlated to prognosis. It was carried on 54 cases of ovarian HGSC who attended the Oncology Centre, Mansoura University, Egypt, from 2012 till 2019. RESULTS: Nearly 60% of cases showed positive PD-L1 expression in tumor cells. Regarding the clinicopathological characteristics, higher PD-L1 expression was found among patients with residual tumor (82.4%) compared to patients with no residual tumor (54.5%), with marginal statistical significance (p 0.07). PD-L1 was significantly associated with CD8 TILs expression. Higher PD-L1 expression was found among tumors with low expression of CD8 TILs with statistically significant difference (p≤0.001). Disease-free survival (DFS) was significantly lower among the group with positive expression of PD-L1 compared to the group with negative expression of PD-L1 (p 0.01), while overall survival (OS) was not associated with PD-L1 expression. On the other hand, the overall survival (OS) in patients with high CD8 expression was significantly higher than patients with low CD8 expression (p 0.043), while DFS was not significantly different among both CD8 TILS groups. CONCLUSIONS: PD-L1 and CD8 TILs may become a promising therapeutic target for patients with ovarian HGSC. More studies are needed to further validate their prognostic effect. Precise identification of patients who will benefit from PD-L1 checkpoint blockade and TILs adaptive immunotherapy is mandatory.


Assuntos
Antígeno B7-H1 , Linfócitos T CD8-Positivos/imunologia , Carcinoma , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/terapia , Adulto , Antígeno B7-H1/análise , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma/mortalidade , Carcinoma/terapia , Egito , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/química , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Prognóstico , Receptor de Morte Celular Programada 1 , Análise de Sobrevida
15.
Nat Commun ; 12(1): 4098, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215730

RESUMO

Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Biópsia , Estudos de Coortes , Feminino , Humanos , Imunoterapia , Masculino , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida
16.
J Immunol ; 207(3): 771-776, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34290103

RESUMO

Tumor-infiltrating regulatory T cells (Tregs) have been extensively studied as therapeutic targets. However, not all infiltrating T cells exert their functions equally, presumably because of their heterogeneity and substantial turnover in tissues. In this study, we hypothesized that intertissue migration underlies the functional heterogeneity of Tregs. To test this, we applied in vivo photolabeling to examine single-cell diversity of immunosuppressive molecules in mouse Tregs migrating to, remaining in, and emigrating from MC38 tumors. Neuropilin-1 (Nrp1) expression was inversely correlated with that of six other molecules associated with Treg function. Unsupervised clustering analyses revealed that clusters containing Tregs that were retained in tumors expressed high levels of the six functional molecules but not of Nrp1. However, these clusters represented only half of the Tregs migrating to the tumor, suggesting evolving heterogeneity of tumor-infiltrating Tregs. Thus, we propose progressive pathways of Treg activation and migration between tumors and draining lymph nodes.


Assuntos
Adenocarcinoma/imunologia , Neoplasias do Colo/imunologia , Fatores de Transcrição Forkhead/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Análise de Célula Única/métodos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Humanos , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais , Neuropilina-1/genética , Neuropilina-1/metabolismo , Fenótipo
17.
Cancer Sci ; 112(9): 3569-3584, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34251747

RESUMO

The abundance and type of immune cells in the tumor microenvironment (TME) significantly influence immunotherapy and tumor progression. However, the role of immune cells in the TME of gastric cancer (GC) is poorly understood. We studied the correlations, proportion, and infiltration of immune and stromal cells in GC tumors. Data analyses showed a significant association of infiltration levels of specific immune cells with the pathological characteristics and clinical outcomes of GC. Furthermore, based on the difference in infiltration levels of immune and stromal cells, GC patients were divided into two categories, those with "immunologically hot" (hot) tumors and those with "immunologically cold" (cold) tumors. The assay for transposase-accessible chromatin using sequencing and RNA sequencing analyses revealed that the hot and cold tumors had altered epigenomic and transcriptional profiles. Claudin-3 (CLDN3) was found to have high expression in the cold tumors and negatively correlated with CD8+ T cells in GC. Overexpression of CLDN3 in GC cells inhibited the expression of MHC-I and CXCL9. Finally, the differentially expressed genes between hot and cold tumors were utilized to generate a prognostic model, which predicted the overall survival of GC as well as patients with immunotherapy. Overall, we undertook a comprehensive analysis of the immune cell infiltration pattern in GC and provided an accurate model for predicting the prognosis of GC patients.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Claudina-3/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Transdução de Sinais/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Quimiocina CXCL9/metabolismo , Claudina-3/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , RNA-Seq , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transcriptoma , Transfecção
18.
Nat Immunol ; 22(8): 1052-1063, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34168370

RESUMO

Immune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (TFR) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating TFR cells. Both TFR cell deficiency and the depletion of TFR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy.


Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Animais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células T Auxiliares Foliculares/imunologia , Microambiente Tumoral/imunologia
19.
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
20.
Cancer Sci ; 112(9): 3484-3490, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34187084

RESUMO

For successful immunotherapy for cancer, it is important to understand the immunological status of tumor antigen-specific CD8+ T cells in the tumor microenvironment during tumor progression. In this study, we monitored the behavior of B16OVA-Luc cells in mice immunized with a model tumor antigen ovalbumin (OVA). Using bioluminescence imaging, we identified the time series of OVA-specific CD8+ T-cell responses during tumor progression: initial progression, immune control, and the escape phase. As a result of analyzing the status of tumor antigen-specific CD8+ cells in those 3 different phases, we found that the expression of NKG2D defines tumor-reacting effector CD8+ T cells. NKG2D may control the fate and TOX expression of tumor-reacting CD8+ T cells, considering that NKG2D blockade in OVA-vaccinated mice delayed the growth of the B16OVA-Luc2 tumor and increased the presence of tumor-infiltrating OVA-specific CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Microambiente Tumoral/imunologia , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/metabolismo , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Bromodesoxiuridina/administração & dosagem , Bromodesoxiuridina/farmacocinética , Interferon gama/deficiência , Interferon gama/genética , Luciferases/metabolismo , Medições Luminescentes/métodos , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/administração & dosagem , Ovalbumina/metabolismo , Neoplasias Cutâneas/patologia , Vacinação/métodos
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