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1.
Front Immunol ; 13: 942862, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091043

RESUMO

The morbidity and mortality of malaria are still high. Programmed cell death-1(PD-1) is an important co-inhibitory factor and CD8 T cells with PD-1 were reported to be exhausted cells. It remains unknown what the role of CD4 T cells expressing PD-1 is and what the upstream regulating molecules of PD-1 in CD4 T cells are. The C57BL/6 mice were injected with Plasmodium yoelii (P. yoelii) in this study. Expressions of PD-1, activation markers, and cytokines were tested. The differentially expressed genes between PD-1+/- CD4 T cells were detected by microarray sequencing. Western blot, chromatin immunoprecipitation (ChIP), siRNA, hypoxia inducible factor-1α (HIF-1α) inducer and inhibitor were used to explore PD-1's upstream molecules, respectively. The proportions of PD-1+ CD4 T cells increased post P. yoelii infection. PD-1+ CD4 T cells expressed more activated surface markers and could produce more cytokines. Nuclear factor of activated T cells 1 (NFATc1) was found to be a key transcription factor to induce PD-1 expression after infection. Both the inducer and the inhibitor of HIF-1α could change the expressions of NFATc1 and PD-1 in vivo and in vitro, respectively. Taken together, P. yoelii infection induced NFATc1 expression by HIF-1α. The highly expressed NFATc1 entered the nucleus and initiated PD-1 expression. PD-1+ CD4 T cells appeared to be more activated and could secrete more cytokines to regulate the host's immune responses against malaria.


Assuntos
Linfócitos T CD4-Positivos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Malária , Fatores de Transcrição NFATC , Plasmodium yoelii , Receptor de Morte Celular Programada 1 , Animais , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Malária/genética , Malária/imunologia , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais
2.
Nature ; 609(7926): 354-360, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35978192

RESUMO

CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion1,2-is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1- exhausted effector T cells3-6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.


Assuntos
Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1 , Proteínas Proto-Oncogênicas c-myb , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Autorrenovação Celular , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Imunoterapia , Selectina L/metabolismo , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-myb/metabolismo , Vírus/imunologia
3.
FEBS Lett ; 596(21): 2721-2735, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36002439

RESUMO

Innate and adaptive immune systems are built-in homeostatic functions of many multicellular organisms and protect the host against foreign pathogens and infections. Dysregulation of the molecular mechanisms of the immune system can result in autoimmune diseases. The immune system can also be harnessed and manipulated to provide targeted cancer therapies, some of them relying on the blockade of immune-checkpoint receptors. Two prominent immune checkpoints, PD-1/PD-L1 and CTLA-4/CD80, comprise receptor-ligand pairs that prevent the host immune cells from attacking host tissues. However, cancer cells upregulate the respective PD-L1 and CD80 ligands for PD-1 and CTLA-4 and thereby evade the host-immune response. Therapeutic drugs that block PD-1/PD-L1 and CTLA-4/CD80 interactions re-enable the immune system to attack cancer cells, but their prognostic biomarker remains challenging. In this review, we discuss how the use of quantitative molecular imaging can be exploited to predict the response to anti-PD-1/PD-L1 therapies and to identify cancer patients who would benefit from them.


Assuntos
Antígeno B7-H1 , Imunoterapia , Neoplasias , Medicina de Precisão , Receptor de Morte Celular Programada 1 , Proteômica , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/imunologia , Medicina de Precisão/métodos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteômica/métodos
4.
Nature ; 609(7926): 369-374, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36045296

RESUMO

Recently, chimeric antigen receptor (CAR)-T cell therapy has shown great promise in treating haematological malignancies1-7. However, CAR-T cell therapy currently has several limitations8-12. Here we successfully developed a two-in-one approach to generate non-viral, gene-specific targeted CAR-T cells through CRISPR-Cas9. Using the optimized protocol, we demonstrated feasibility in a preclinical study by inserting an anti-CD19 CAR cassette into the AAVS1 safe-harbour locus. Furthermore, an innovative type of anti-CD19 CAR-T cell with PD1 integration was developed and showed superior ability to eradicate tumour cells in xenograft models. In adoptive therapy for relapsed/refractory aggressive B cell non-Hodgkin lymphoma (ClinicalTrials.gov, NCT04213469 ), we observed a high rate (87.5%) of complete remission and durable responses without serious adverse events in eight patients. Notably, these enhanced CAR-T cells were effective even at a low infusion dose and with a low percentage of CAR+ cells. Single-cell analysis showed that the electroporation method resulted in a high percentage of memory T cells in infusion products, and PD1 interference enhanced anti-tumour immune functions, further validating the advantages of non-viral, PD1-integrated CAR-T cells. Collectively, our results demonstrate the high safety and efficacy of non-viral, gene-specific integrated CAR-T cells, thus providing an innovative technology for CAR-T cell therapy.


Assuntos
Imunoterapia Adotiva , Linfoma de Células B , Receptores de Antígenos Quiméricos , Animais , Antígenos CD19/imunologia , Eletroporação , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Células T de Memória/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva , Análise de Célula Única , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Front Immunol ; 13: 932627, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967356

RESUMO

Background: Despite immune cell dysregulation being an important event preceding the onset of rheumatoid arthritis (RA), the phenotype of T and B cells in preclinical RA is less understood. The aim of this study was to characterize T and B cell populations in RA patients and their autoantibody (aAb) negative and positive first-degree relatives (FDR). Methods: Cryopreserved peripheral blood mononuclear cells (PBMCs) collected at scheduled visits from aAb-(n=25), and aAb+ FDR (n=10) and RA patients (n=13) were thawed and stained using optimized antibody cocktails as per a specific 13-color T or B cell panel. Immunophenotyping was performed using a Cytoflex LX (Beckman-Coulter) flow cytometer and FlowJo software was used for analyzing the frequency of immune cell populations. Results: Multicolor flow cytometry experiments identified an increased TIGIT expression in circulating lymphocytes of aAb+ FDR and RA patients, relative to aAb- FDR (P<0.01). These TIGIT+ T cells exhibited a memory phenotype and expressed high levels of PD-1, ICOS, HLA-DR, CXCR3 and CXCR5. Moreover, increased TIGIT+ CD4 T cell frequency correlated with the frequency of PD-1+ CD4 T cells (r = 0.4705: P = 0.0043) and circulating levels of ACPA and RF. We also identified a decreased frequency of CD27+IgD- switched memory B cells in RA patients (P < 0.01), while increased frequency of TIGIT+ CD4 T cells in FDR correlated with the frequency of PD1+PTEN+ B cells (r = 0.6838, P = 0.0004) and autoantibody positivity (P = 0.01). Conclusion: We demonstrate TIGIT as a distinct CD4 T cell marker for differentiating aAb- FDR from aAb+FDR and might play a critical role in regulating T and B cell crosstalk in preclinical RA.


Assuntos
Artrite Reumatoide , Linfócitos T CD4-Positivos , Receptores Imunológicos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Subpopulações de Linfócitos T/imunologia
6.
Front Immunol ; 13: 902167, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36003385

RESUMO

Background: As a recognized highly immunogenic tumor, immune checkpoint blockades (ICB) have been widely used as a systemic treatment option for melanoma. However, only about half of treated patients could benefit from it in Caucasians, and only about 15% in Chinese melanoma patients. Robust predictive biomarkers are needed. HHLA2, a new-found member of B7 family, is generally expressed in kinds of tumors, such as melanoma. This study focuses on illustrating the prognostic value of HHLA2 in melanoma immunotherapy and its association with tumor-infiltrating lymphocytes. Methods: HHLA2 expression in pan-cancer and the association with prognosis and immune microenvironment were identified by analyzing gene expression profiles from TCGA database with selected bioinformatics tools and methods. Tumor tissues from 81 cases with advanced and unresectable melanoma were collected for detecting HHLA2 and CD8 levels by immunohistochemistry. Results: HHLA2 was found to be ubiquitously expressed in pan-cancer with high level and correlate with the prognosis of patients. Further comprehensive analysis from TCGA database demonstrated that the highly expressed HHLA2 was remarkably correlated with better prognosis, high infiltration status of various immune-active cells and immune activated pathways in skin cutaneous melanoma (SKCM). Moreover, immunohistochemistry (IHC) analyses of FFPE tissue from melanoma patients revealed that HHLA2 high expression was strongly related to improved response to ICB and indicated a longer progression-free survival (PFS) and overall survival (OS). Besides, HHLA2 expression was found to have a positive association with the density of CD8+ TILs. Conclusion: Our findings revealed that high expression of HHLA2 has important values in predicting the response to ICB and indicating improved PFS and OS in patients with advanced and unresectable melanoma, suggesting that HHLA2 may serve as a costimulatory ligand in melanoma, which renders it as an ideal biomarker for immunotherapy.


Assuntos
Imunoglobulinas , Melanoma , Neoplasias Cutâneas , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Humanos , Imunoglobulinas/genética , Imunoterapia , Melanoma/terapia , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Microambiente Tumoral
7.
Front Immunol ; 13: 869768, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774790

RESUMO

Chronic viral infections where the antigen persists long-term, induces an exhaustion phenotype in responding T cells. It is now evident that immune checkpoints on T cells including PD-1, CTLA-4, and PSGL-1 (Selplg) are linked with the differentiation of exhausted cells. Chronic T cell receptor signaling induces transcriptional signatures that result in the development of various exhausted T cell subsets, including the stem-like T cell precursor exhausted (Tpex) cells, which can be reinvigorated by immune checkpoint inhibitors (ICIs). While PSGL-1 has been shown to inhibit T cell responses in various disease models, the cell-intrinsic function of PSGL-1 in the differentiation, maintenance, and reinvigoration of exhausted T cells is unknown. We found Selplg-/- T cells had increased expansion in melanoma tumors and in early stages of chronic viral infection. Despite their increase, both WT and Selplg-/- T cells eventually became phenotypically and functionally exhausted. Even though virus-specific Selplg-/- CD4+ and CD8+ T cells were increased at the peak of T cell expansion, they decreased to lower levels than WT T cells at later stages of chronic infection. We found that Selplg-/- CD8+ Tpex (SLAMF6hiTIM3lo, PD-1+TIM3+, TOX+, TCF-1+) cell frequencies and numbers were decreased compared to WT T cells. Importantly, even though virus-specific Selplg-/- CD4+ and CD8+ T cells were lower, they were reinvigorated more effectively than WT T cells after anti-PD-L1 treatment. We found increased SELPLG expression in Hepatitis C-specific CD8+ T cells in patients with chronic infection, whereas these levels were decreased in patients that resolved the infection. Together, our findings showed multiple PSGL-1 regulatory functions in exhausted T cells. We found that PSGL-1 is a cell-intrinsic inhibitor that limits T cells in tumors and in persistently infected hosts. Additionally, while PSGL-1 is linked with T cell exhaustion, its expression was required for their long-term maintenance and optimal differentiation into Tpex cells. Finally, PSGL-1 restrained the reinvigoration potential of exhausted CD4+ and CD8+ T cells during ICI therapy. Our findings highlight that targeting PSGL-1 may have therapeutic potential alone or in combination with other ICIs to reinvigorate exhausted T cells in patients with chronic infections or cancer.


Assuntos
Linfócitos T CD8-Positivos , Coriomeningite Linfocítica , Glicoproteínas de Membrana , Receptor de Morte Celular Programada 1 , Linfócitos T CD8-Positivos/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Coriomeningite Linfocítica/tratamento farmacológico , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
8.
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
9.
J Immunother Cancer ; 10(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35793874

RESUMO

BACKGROUND: Immunotherapies targeting programmed cell death-1 (PD-1) and its ligands have improved clinical outcomes for advanced melanoma. However, many tumors exhibit primary resistance or acquire secondary resistance after an initial positive response. The mechanisms of resistance are not well understood, and no validated predictive biomarkers are available. This exploratory study aimed to characterize baseline differences and molecular changes arising during treatment in acral and mucosal melanomas that exhibited primary or secondary resistance to anti-PD-1 monotherapy. METHODS: This was an observational retrospective study of 124 patients who had been treated for metastatic acral or mucosal melanoma with anti-PD-1 monotherapy. Tumor samples were collected at baseline (all patients) and post-treatment (resistant tumors only) and were assayed by immunohistochemistry, whole-exome sequencing, and RNA sequencing. RESULTS: At baseline, more non-progressor than resistant tumors exhibited expression of PD-L1, immune cell infiltration, and high tumor mutational burden (TMB); baseline PD-L1 expression was also more common in secondary-resistant than in primary-resistant tumors as well as in late versus early secondary-resistant tumors. Non-progressor tumors also had higher median baseline expression of an 18-gene T cell-inflamed gene expression profile (TcellinfGEP). Among resistant tumors, the proportion of PD-L1-positive melanomas and the expression of the TcellinfGEP mRNA signature increased during treatment, while the expression of mRNA signatures related to WNT and INFA1 signaling decreased. There was evidence for greater changes from baseline in secondary-resistant versus primary-resistant tumors for some markers, including expression of RAS-related and WNT-related mRNA signatures and density of CD11c+ and FOXP3+ T cells. Greater changes in CD11c+ cell density were observed in early compared with late secondary-resistant tumors. CONCLUSIONS: Our findings suggest that TcellinfGEP and PD-L1 expression, TMB, immune cell infiltration, and RAS and WNT signaling warrant further investigation as potential mechanisms and/or biomarkers of anti-PD-1 therapy resistance in acral and mucosal melanomas. Confirmation of these findings in larger populations is needed.


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Biomarcadores/análise , Humanos , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , RNA Mensageiro/biossíntese , Estudos Retrospectivos
10.
BMC Cancer ; 22(1): 738, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794593

RESUMO

BACKGROUND: Immune checkpoint blockade (ICB) only works well for a certain subset of patients with non-small cell lung cancer (NSCLC). Therefore, biomarkers for patient stratification are desired, which can suggest the most beneficial treatment. METHODS: In this study, three datasets (GSE126044, GSE135222, and GSE136961) of immunotherapy from the Gene Expression Omnibus (GEO) database were analyzed, and seven intersected candidates were extracted as potential biomarkers for ICB followed by validation with The Cancer Genome Atlas (TCGA) dataset and the in-house cohort data. RESULTS: Among these candidates, we found that human leukocyte antigen-DR alpha (HLA-DRA) was downregulated in NSCLC tissues and both tumor and immune cells expressed HLA-DRA. In addition, HLA-DRA was associated with an inflamed tumor microenvironment (TME) and could predict the response to ICB in NSCLC. Moreover, we validated the predictive value of HLA-DRA in immunotherapy using an in-house cohort. Furthermore, HLA-DRA was related to the features of inflamed TME in not only NSCLC but also in most cancer types. CONCLUSION: Overall, HLA-DRA could be a promising biomarker for guiding ICB in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Cadeias alfa de HLA-DR , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Biomarcadores Tumorais/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Cadeias alfa de HLA-DR/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Fatores Imunológicos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral
11.
Gastroenterology ; 163(4): 965-981.e31, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35738329

RESUMO

BACKGROUND & AIMS: Exhaustion of CD8 T cells has been suggested to inform different clinical outcomes in Crohn's disease, but detailed analyses are lacking. This study aimed to identify the role of exhaustion on a single-cell level and identify relevant CD8 T cell populations in Crohn's disease. METHODS: Blood and intestinal tissue from 58 patients with Crohn's disease (active disease or remission) were assessed for CD8 T cell expression of exhaustion markers and their cytokine profile by highly multiplexed flow and mass cytometry. Key disease-associated subsets were sorted and analyzed by RNA sequencing. CD39 inhibition assays were performed in vitro. RESULTS: Activated CD39+ and CD39+PD-1+ CD8 T cell subsets expressing multiple exhaustion markers were enriched at low frequency in active Crohn's disease. Their cytokine production capacity was inversely linked to the Harvey-Bradshaw Index. Subset-level protein and transcriptome profiling revealed co-existence of effector and exhaustion programs in CD39+ and CD39+ PD-1+CD8 T cells, with CD39+ cells likely originating from the intestine. CD39 enzymatic activity controlled T cell cytokine production. Importantly, transcriptional exhaustion signatures were enriched in remission in CD39-expressing subsets with up-regulation of TOX. Subset-level transcriptomics revealed a CD39-related gene module that is associated with the clinical course. CONCLUSIONS: These data showed a role for the exhaustion of peripheral CD39-expressing CD8 T cell subsets in Crohn's disease. Their low frequency illustrated the utility of single-cell cytometry methods for identification of relevant immune populations. Importantly, the link of their exhaustion status to the clinical activity and their specific gene signatures have implications for exhaustion-based personalized medicine approaches.


Assuntos
Apirase , Linfócitos T CD8-Positivos , Doença de Crohn , Apirase/sangue , Apirase/genética , Apirase/imunologia , Biomarcadores/sangue , Linfócitos T CD8-Positivos/imunologia , Doença de Crohn/sangue , Doença de Crohn/genética , Doença de Crohn/imunologia , Citocinas/imunologia , Humanos , Prognóstico , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Subpopulações de Linfócitos T
12.
Nat Commun ; 13(1): 3739, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35768432

RESUMO

Tumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an "epigenetic checkpoint" for tumor immunity.


Assuntos
Linfócitos T CD8-Positivos , Melanoma , Metiltransferases , Receptor de Morte Celular Programada 1 , Proteínas Repressoras , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Epigênese Genética , Humanos , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma/genética , Melanoma/imunologia , Melanoma/terapia , Metiltransferases/antagonistas & inibidores , Metiltransferases/genética , Metiltransferases/imunologia , Metiltransferases/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
13.
J Pathol Clin Res ; 8(5): 458-469, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35762092

RESUMO

Programmed cell death-1 (PD-1) and its ligand (PD-L1) are significant mediators of immune suppression in the tumor microenvironment. We focused on the immunological impact of PD-1/PD-L1 signaling during tumor progression in colorectal carcinoma (CRC) and its association with resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal carcinoma (LAd-RC). Histopathological and immunohistochemical analyses of 100 CRC cases (including 34 RC) without NCRT and 109 NCRT-treated LAd-RC cases were performed. Membranous tumoral PD-L1 expression was identified in 9 of 100 (9%) CRC cases, including 1 of 34 (2.9%) RC cases, but PD-L1 immunopositivity was not associated with any clinicopathological factors, with the exception of deficient mismatch repair (dMMR) status. In contrast, stromal PD-L1+ immune cells, which frequently exhibited coexpression of PD-1 and CD8 markers, were significantly correlated with tumor vessel invasion, nuclear ß-catenin+ tumor budding cancer stem cell (CSC)-like features, and unfavorable prognosis. In the LAd-RC cases, stromal CD8+ (but not PD-L1+) immune cell infiltration in pretreatment-biopsied samples was significantly and positively associated with therapeutic efficacy. After NCRT, tumoral PD-L1 expression was observed in only 2 of 83 (2.4%) tumors, independent of dMMR status, whereas high stromal PD-L1+ and tumoral nuclear ß-catenin positivity were significantly linked to a poor response to NCRT and high tumor budding features. In addition, high stromal PD-L1 immunoreactivity was significantly associated with poorer overall survival. In conclusion, a combination of stromal PD-L1+ immune cells and nuclear ß-catenin+ tumor budding may contribute to tumor progression in CRC and resistance to NCRT in LAd-RC, through formation of niche-like lesions that exhibit immune resistance and CSC properties.


Assuntos
Antígeno B7-H1 , Resistencia a Medicamentos Antineoplásicos , Receptor de Morte Celular Programada 1 , Tolerância a Radiação , Neoplasias Retais , beta Catenina , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Núcleo Celular/genética , Núcleo Celular/imunologia , Quimiorradioterapia Adjuvante , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Terapia Neoadjuvante , Prognóstico , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Tolerância a Radiação/genética , Tolerância a Radiação/imunologia , Neoplasias Retais/genética , Neoplasias Retais/imunologia , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , beta Catenina/genética , beta Catenina/imunologia
14.
Front Immunol ; 13: 871362, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757718

RESUMO

Lower extremity arteriosclerosis obliterans (LEASO) is a vascular disease that may result in adult limb loss worldwide. CD4+T cell-mediated immunity plays a significant role in LEASO. The T cell immunoglobulin and mucin domain 3 (Tim-3) and inhibitory receptor programmed cell death-1 (PD-1) are well-known immune checkpoints that play crucial roles in regulating CD4+T cell activation or tolerance. In this study, blood mononuclear cells were isolated from the blood samples of healthy controls and patients who were diagnosed with LEASO for the first time [stage III or IV according to the Fontaine classification system and had not received drugs (except for heparin) or surgery treatment]. We concluded the higher proportion of Tim-3+PD-1+CD4+T cells in human higher stage LEASO, and oxidized low-density lipoprotein increased Tim-3 and PD-1 co-expression by activating CD4+T cells in a dose- dependent manner. Tim-3+PD-1+CD4+T cells displayed a more active status and produced more anti-atherogenic cytokines compared to Tim-3-PD-1-CD4+T cells. Apart from the increased frequency, the altered function of Tim-3+PD-1+CD4+T cells was also observed in LEASO compared to those from healthy controls. These in vitro results indicated that Tim-3 and PD-1 might be promising early warning targets of higher stage LEASO. In addition, the blockade of Tim-3 and PD-1 signaling pathways aggravated the pro-atherogenic Th1 responses in LEASO, further suggesting that the cardiovascular safety must be a criterion considered in using immune checkpoint inhibitors to reverse T cell exhaustion during tumors and chronic viral infections.


Assuntos
Arteriosclerose Obliterante , Linfócitos T CD4-Positivos , Receptor Celular 2 do Vírus da Hepatite A , Receptor de Morte Celular Programada 1 , Adulto , Arteriosclerose Obliterante/imunologia , Linfócitos T CD4-Positivos/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Extremidade Inferior , Receptor de Morte Celular Programada 1/imunologia
15.
Front Immunol ; 13: 866179, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720419

RESUMO

Infection with Trypanosoma cruzi remains the most important neglected zoonosis in Latin America. This infection does not lead to specific symptoms in the acute phase, but chronic infection can result in Chagas disease (CD) with cardiac and/or gastrointestinal manifestations that can lead to death. CD8+ T cells are highly effective and essential to control this infection, but fail to eliminate all parasites. In this study, we show that the CD8+ T cells are modulated by the transient induction of co-inhibitory receptors during acute infection of C57BL/6 mice. Therapeutic intervention strategies with blocking antibodies only had a marginal effect on the elimination of parasite reservoirs. Only long-term chronic infection gave rise to dysfunctional CD8+ T cells, which were characterized by high expression of the inhibitory receptor PD-1 and the co-expression of the transcription factor TOX, which plays a crucial role in the maintenance of the exhausted phenotype. PD-1+ TOX+ CD8+ T cells isolated from the site of infection produced significantly less IFN-γ, TNF-α and Granzyme B than their PD-1- TOX- CD8+ T cell counterparts after T. cruzi-specific stimulation ex vivo. Taken together, we provide evidence that, in the context of experimental infection of mice, the magnitude of the CD8+ T cell response in the acute phase is sufficient for parasite control and cannot be further increased by targeting co-inhibitory receptors. In contrast, persistent long-term chronic infection leads to an increase of exhausted T cells within the tissues of persistence. To our knowledge, this is the first description of infection-induced CD8+ T cells with an exhausted phenotype and reduced cytokine production in muscles of T. cruzi-infected mice.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Animais , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo
16.
J Immunother Cancer ; 10(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35728870

RESUMO

BACKGROUND: The repression or downregulation of programmed death-ligand 1 (PD-L1) can release its inhibition of T cells and activate antitumor immune responses. Although PD-1 and PD-L1 antibodies are promising treatments for diverse tumor types, their inherent disadvantages and immune-related adverse events remain significant issues. The development of small molecule inhibitors targeting the interaction surface of PD-1 and PD-L1 has been reviving, yet many challenges remain. To address these issues, we aimed to find small molecules with durable efficacy and favorable biosafety that alter PD-L1 surface expression and can be developed into a promising alternative and complementary therapy for existing anti-PD-1/PD-L1 therapies. METHODS: Cell-based screen of 200 metabolic molecules using a high-throughput flow cytometry assay of PD-L1 surface expression was conducted, and L-5-hydroxytryptophan (L-5-HTP) was found to suppress PD-L1 expression induced by interferon gamma (IFN-γ). Inhibition of PD-L1 induction and antitumor effect of L-5-HTP were evaluated in two syngeneic mouse tumor models. Flow cytometry was performed to investigate the change in the tumor microenvironment caused by L-5-HTP treatment. RESULTS: We discovered that L-5-HTP suppressed IFN-γ-induced PD-L1 expression in tumor cells transcriptionally, and this effect was directly due to itself. Mechanistically, L-5-HTP inhibited IFN-γ-induced expression of RTK ligands and thus suppressed phosphorylation-mediated activation of RTK receptors and the downstream MEK/ERK/c-JUN signaling cascade, leading to decreased PD-L1 induction. In syngeneic mouse tumor models, treatment with 100 mg/kg L-5-HTP (intraperitoneal) inhibited PD-L1 expression and exhibited antitumor effect. L-5-HTP upregulated the ratio of granzyme B+ CD8+ activated cytotoxic T cells. An intact immune system and PD-L1 expression was critical for L-5-HTP to exert its antitumor effects. Furthermore, L-5-HTP acted synergistically with PD-1 antibody to improve anticancer effect. CONCLUSION: Our study illustrated L-5-HTP's inhibitory effect on PD-L1 induction stimulated by IFN-γ in tumor cells and also provided insight into repurposing L-5-HTP for use in tumor immunotherapy.


Assuntos
5-Hidroxitriptofano , Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , 5-Hidroxitriptofano/farmacologia , Animais , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Humanos , Interferon gama/metabolismo , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/imunologia
17.
Clin Chim Acta ; 533: 71-78, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35709988

RESUMO

As a subset of advanced melanoma patients derive long-term benefit from anti-PD-1 therapy, early identification of non-responsiveness would enable an early switch to next line therapies. This study assessed if an early increase in S100B or lactate dehydrogenase (LDH) could be predictive for non-responsiveness to anti-PD-1. We retrospectively analysed advanced melanoma patients treated with anti-PD-1 monotherapy. Serum S100B and LDH levels were measured at baseline and before every infusion. Non-response was defined as progression or death at 6 months. Marker cut-offs were defined based on > 95% specificity and feasibility in clinical practice. For validation an independent cohort was analysed. In total, 313 patients were included (166 patients in training cohort, 147 patients in validation cohort). Increase of > 50% in LDH or > 100% in S100B above upper limit of normal at week 6 compared to baseline was determined as criterion to positively test for non-responsiveness. In the validation cohort, obtained specificity of the combination test was > 95% with a positive predictive value of 82%; obtained sensitivity was lower (21%), with a negative predictive value of 55%. Early increase in S100B or LDH is a strong parameter for non-responsiveness to anti-PD-1 in advanced melanoma. Prospective confirmation is needed before clinical implementation.


Assuntos
Melanoma , Neoplasias Cutâneas , Anticorpos/uso terapêutico , Biomarcadores Tumorais , Humanos , L-Lactato Desidrogenase , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , Estudos Retrospectivos , Subunidade beta da Proteína Ligante de Cálcio S100 , Neoplasias Cutâneas/diagnóstico
18.
Biochem Biophys Res Commun ; 613: 12-18, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35526483

RESUMO

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system worldwide. To date, immune checkpoint inhibitors (including PD-1/PD-L1) have been applied to treat patients with bladder cancer in the clinic and achieved the promising outcome. Further improvement of the anticancer efficiency of these immune therapies is crucial for bladder cancer. Our previous RNA-seq data on CBX7 (GSE185630) suggested that CBX7 might repress PD-L1 expression and PD-1 checkpoint pathway in cancer. In this study, we revealed that CBX7 downregulated the expression of POU2F2 that indirectly repressed the PD-L1 in BC cells. Depletion of CBX7 resulted in resistance to PD-1 blockade in bladder cancer. Collectively, our results suggested that the CBX7/POU2F2/PD-L1 axis plays an important role in determining the antitumor effect of PD-1 blockade in bladder cancer.


Assuntos
Antígeno B7-H1 , Fator 2 de Transcrição de Octâmero , Complexo Repressor Polycomb 1 , Neoplasias da Bexiga Urinária , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Fator 2 de Transcrição de Octâmero/imunologia , Complexo Repressor Polycomb 1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
19.
Int J Cancer ; 151(8): 1321-1334, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35579980

RESUMO

Hepatocellular carcinoma (HCC) is a severe disease with high mortality and global incidence. However, the interaction between the gut microbiome and combined immunotherapy for HCC is yet unclear. In this prospective clinical study, patients with unresectable HCC who had not received systemic treatment previously were recruited. Fecal and serum samples were collected at the baseline point and before each subsequent administration as specified. Between 20 October 2019 and 2 February 2021, 61 patients were screened for eligibility, of whom 35 patients were finally included in this study. Alpha diversity of fecal samples from patients who responded to immunotherapy was higher than that of nonresponders at baseline. However, the prominent alpha-diversity between responders and nonresponders became similar as early as week 6 after treatment. The beta diversity of intergroup did not show significant difference at the ninth week after treatment. Alpha-d-Glucose was the only serum metabolite that differed between the responders and nonresponders after 3 months. Responder-enriched Ruminococcus showed a positive correlation with serum galactaric acid, while Klebsiella was positively associated with 3-methylindole and lenticin (all P < .01). The machine learning classifier based on serum metabolites were more able to discriminate HCC patients who potentially benefited from immunotherapy at baseline (AUC 0.793, 95% CI: 0.632-0.954) than the classifier of gut microbiome. In conclusion, gut microbiome biomarkers are associated with the response to anti-PD-1 based immunotherapy in HCC patients. Classifiers based on gut microbiota and serum metabolites are feasible.


Assuntos
Carcinoma Hepatocelular , Microbioma Gastrointestinal , Neoplasias Hepáticas , Microbiota , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Neoplasias Hepáticas/tratamento farmacológico , Metaboloma , Receptor de Morte Celular Programada 1/imunologia , Estudos Prospectivos
20.
Future Oncol ; 18(20): 2483-2487, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35543482

RESUMO

WHAT IS THIS SUMMARY ABOUT?: In this article, we discuss the results of our clinical study that looked at the use of two immunotherapy drugs for the treatment of advanced melanoma. Melanoma is considered advanced when it is no longer curable with surgery. WHAT HAPPENED IN THE STUDY?: The two-drug combination, pembrolizumab and ipilimumab, was given to people with melanoma who's cancer had progressed. This study looked at how effective these two drugs were in terms of controlling the melanoma, as well their safety. These results from the study were then compared to the results from previous studies looking at melanoma treatment with ipilimumab on its own, which previously had been the most commonly used drug. WHAT WERE THE RESULTS?: The study, originally published in the Journal of Clinical Oncology, showed that combination treatment with pembrolizumab and ipilimumab was more likely to be effective than ipilimumab on its own. Not all of the study participants benefited, but many of those who did benefit experienced long-term remission from their melanoma without needing more treatment. Around 1/3 of the participants in the study had their tumors shrink compared to previous studies, which showed that ipilimumab was expected to shrink 1 in 8 tumors. The rates of side effects were similar with the pembrolizumab and ipilimumab combination compared to ipilimumab alone.


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Anticorpos Monoclonais Humanizados , Humanos , Ipilimumab/efeitos adversos , Idioma , Melanoma/tratamento farmacológico , Melanoma/patologia , Receptor de Morte Celular Programada 1/imunologia
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