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1.
Nat Immunol ; 24(8): 1308-1317, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37365384

RESUMO

Virtual memory T (TVM) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although TVM cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a TVM cell-originated CD44super-high(s-hi)CD49dlo CD8+ T cell subset with features of tissue residency. These cells are transcriptionally, phenotypically and functionally distinct from conventional CD8+ TVM cells and can cause alopecia areata. Mechanistically, CD44s-hiCD49dlo CD8+ T cells could be induced from conventional TVM cells by interleukin (IL)-12, IL-15 and IL-18 stimulation. Pathogenic activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-dependent innate-like cytotoxicity, which was further augmented by IL-15 stimulation and triggered disease onset. Collectively, these data suggest an immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.


Assuntos
Alopecia em Áreas , Linfócitos T CD8-Positivos , Humanos , Interleucina-15 , Memória Imunológica , Subpopulações de Linfócitos T
2.
Nat Immunol ; 23(1): 13-22, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34354279

RESUMO

During microbial infection, pre-existing memory CD8+ T cells that are not specific for the infecting pathogens can be activated by cytokines without cognate antigens, termed bystander activation. Studies in mouse models and human patients demonstrate bystander activation of memory CD8+ T cells, which exerts either protective or detrimental effects on the host, depending on the infection model or disease. Research has elucidated mechanisms underlying the bystander activation of CD8+ T cells in terms of the responsible cytokines and the effector mechanisms of bystander-activated CD8+ T cells. In this Review, we describe the history of research on bystander CD8+ T cell activation as well as evidence of bystander activation. We also discuss the mechanisms and immunopathological roles of bystander activation in various microbial infections.


Assuntos
Efeito Espectador/imunologia , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Microbiota/imunologia , Animais , Antígenos/imunologia , Citocinas/imunologia , Humanos , Memória Imunológica/imunologia , Inflamação/imunologia
3.
J Immunol ; 208(8): 1901-1911, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35346965

RESUMO

In bystander activation, pre-existing memory CD8+ T cells unrelated to the infecting microbes are activated by cytokines without cognate Ags. The detailed mechanisms and unique gene signature of bystander activation remain to be elucidated. In this study, we investigated bystander activation of OT-1 memory cells in a mouse model of influenza infection. We found that OT-1 memory cells are activated with upregulation of granzyme B and IFN-γ, during PR8 (A/Puerto Rico/8/1934) infection, and IL-15 is a critical cytokine for bystander activation. In transcriptomic analysis, the IFN-induced gene signature was upregulated in bystander-activated OT-1 memory cells during PR8 infection but not in the presence of TCR stimulation. Among the IFN-induced genes, upregulation of IFN-induced transmembrane protein 3 (IFITM3) distinguished bystander-activated OT-1 memory cells from TCR-activated OT-1 memory cells. Therefore, we reveal that bystander-activated memory CD8+ T cells have a unique transcriptomic feature compared with TCR-activated memory CD8+ T cells. In particular, IFITM3 upregulation can be used as a marker of bystander-activated memory CD8+ T cells at early infection.


Assuntos
Linfócitos T CD8-Positivos , Influenza Humana , Animais , Citocinas/metabolismo , Humanos , Memória Imunológica , Interleucina-15/metabolismo , Ativação Linfocitária , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/metabolismo
4.
Thorax ; 77(8): 769-780, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-34853159

RESUMO

BACKGROUND: Tumour-unrelated, virus-specific bystander CD8+ T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet. METHODS: We studied the characteristics of bystander CD8+ TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy. RESULTS: We show that bystander CD8+ TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8+ TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8+ TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8+ TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment. CONCLUSION: Thus, the study demonstrates that bystander CD8+ TILs can be repurposed by IL-15 for tumour immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Interferon gama/metabolismo , Interleucina-15/metabolismo , Interleucina-15/farmacologia , Neoplasias Pulmonares/patologia , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Microambiente Tumoral
5.
J Allergy Clin Immunol ; 148(4): 996-1006.e18, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34339730

RESUMO

BACKGROUND: Our understanding of adaptive immune responses in patients with coronavirus disease 2019 (COVID-19) is rapidly evolving, but information on the innate immune responses by natural killer (NK) cells is still insufficient. OBJECTIVE: We aimed to examine the phenotypic and functional status of NK cells and their changes during the course of mild and severe COVID-19. METHODS: We performed RNA sequencing and flow cytometric analysis of NK cells from patients with mild and severe COVID-19 at multiple time points in the course of the disease using cryopreserved PBMCs. RESULTS: In RNA-sequencing analysis, the NK cells exhibited distinctive features compared with healthy donors, with significant enrichment of proinflammatory cytokine-mediated signaling pathways. Intriguingly, we found that the unconventional CD56dimCD16neg NK-cell population expanded in cryopreserved PBMCs from patients with COVID-19 regardless of disease severity, accompanied by decreased NK-cell cytotoxicity. The NK-cell population was rapidly normalized alongside the disappearance of unconventional CD56dimCD16neg NK cells and the recovery of NK-cell cytotoxicity in patients with mild COVID-19, but this occurred slowly in patients with severe COVID-19. CONCLUSIONS: The current longitudinal study provides a deep understanding of the NK-cell biology in COVID-19.


Assuntos
COVID-19/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , SARS-CoV-2/imunologia , Adulto , COVID-19/patologia , Humanos , Células Matadoras Naturais/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA-Seq
6.
Hepatology ; 71(3): 955-971, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31353502

RESUMO

BACKGROUND AND AIMS: Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4-1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor-infiltrating CD8+ T cells (CD8+ tumor-infiltrating lymphocytes [TILs]) and its association with distinct T-cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). APPROACH AND RESULTS: Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA-sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4-1BB was most prominently expressed on CD8+ TILs. 4-1BB expression was almost exclusively detected on CD8+ T cells in the tumor-especially on programmed death 1 (PD-1)high cells and not PD-1int and PD-1neg cells. Compared to PD-1int and 4-1BBneg PD-1high CD8+ TILs, 4-1BBpos PD-1high CD8+ TILs exhibited higher levels of tumor reactivity and T-cell activation markers and significant enrichment for T-cell activation gene signatures. Per-patient analysis revealed positive correlations between percentages of 4-1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T-cell activation. Among highly exhausted PD-1high CD8+ TILs, 4-1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4-1BB-related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4-1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti-PD-1-mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T-cell activation. CONCLUSION: 4-1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4-1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T-cell activation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , Idoso , Carcinoma Hepatocelular/tratamento farmacológico , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistas , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/análise
7.
Liver Int ; 41(4): 764-776, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33548061

RESUMO

BACKGROUND: The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8+ T cells (CD8+ TILs) from ICC patients. METHODS: From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing. RESULTS: When compared to peripheral CD8+ T cells, the CD8+ TILs included significantly higher proportions of the CD69+ CD103- and CD69+ CD103+ TRM-like subsets (P < .001 for both). Relative to CD69- and CD69+ CD103- cells, the CD69+ CD103+ CD8+ TILs harboured higher levels of T-cell markers representing tumour specificity (ie CD39), proliferation (ie Ki-67) and T-cell activation (ie HLA-DR and CD38) (all P < .001). Moreover, compared to the stroma, the tumour margin and core density each had a significantly higher density of CD103+ CD8+ TILs (P < .001 for both). ICCs with high proportions of CD69+ CD103+ cells displayed higher levels of parameters associated with response to immune checkpoint inhibitors (ICIs)-including number of CD8+ TIL infiltrates (P = .019), PD-L1 expression in the tumour (P = .046) and expression of the T cell-inflamed gene signature (P < .001). ICCs with lower proportions of CD69+ CD103+ CD8+ TILs exhibited significant enrichment of genes related to the Wnt/ß-catenin (P < .001) and TGF-ß pathways (P = .002). CONCLUSION: CD69+ CD103+ TRM-like CD8+ TILs represent prominent tumour-specific immune responses and hold promise as a potential therapeutic target in ICC patients. Differential TRM-related features of ICCs may help develop future immunotherapeutic strategies such as maximizing TRM responses or inhibiting pathways contributing to immune evasion.


Assuntos
Linfócitos T CD8-Positivos , Colangiocarcinoma , Humanos , Memória Imunológica , Imunoterapia , Ativação Linfocitária , Linfócitos do Interstício Tumoral
8.
Cell Rep ; 42(3): 112236, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36897779

RESUMO

Subsets of the human CD8+ T cell population express inhibitory NK cell receptors, such as killer immunoglobulin-like receptors (KIRs) and NKG2A. In the present study, we examine the phenotypic and functional characteristics of KIR+CD8+ T cells and NKG2A+CD8+ T cells. KIRs and NKG2A tend to be expressed by human CD8+ T cells in a mutually exclusive manner. In addition, TCR clonotypes of KIR+CD8+ T cells barely overlap with those of NKG2A+CD8+ T cells, and KIR+CD8+ T cells are more terminally differentiated and replicative senescent than NKG2A+CD8+ T cells. Among cytokine receptors, IL12Rß1, IL12Rß2, and IL18Rß are highly expressed by NKG2A+CD8+ T cells, whereas IL2Rß is expressed by KIR+CD8+ T cells. IL-12/IL-18-induced production of IFN-γ is prominent in NKG2A+CD8+ T cells, whereas IL-15-induced NK-like cytotoxicity is prominent in KIR+CD8+ T cells. These findings suggest that KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations with different cytokine responsiveness.


Assuntos
Linfócitos T CD8-Positivos , Receptores Imunológicos , Humanos , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Receptores KIR , Receptores de Células Matadoras Naturais
9.
Cell Rep ; 36(4): 109438, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34320338

RESUMO

During microbial infection, bystander CD8+ T cells that are not specific to infecting pathogens can be activated by interleukin (IL)-15. However, the tissue-homing properties of bystander-activated CD8+ T cells have not been elucidated. Here, we examine the effects of IL-15 on the expression of chemokine receptors on CD8+ T cells and their migration. IL-15 upregulates CCR5 in memory CD8+ T cells in the absence of T cell receptor (TCR) stimulation and enhances CCR5-dependent migration. IL-15-induced CCR5 upregulation is abrogated by TCR stimulation, indicating that CCR5 is upregulated in bystander-activated CD8+ T cells. Moreover, CCR5 signals increase proliferation and cytotoxic protein expression in IL-15-treated memory CD8+ T cells, although the increase has a small extent. CCR5 upregulation in bystander-activated CD8+ T cells is associated with severe liver injury in patients with acute hepatitis A. Altogether, the results indicate that CCR5 upregulation by IL-15 mediates the migration of bystander-activated CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Movimento Celular , Memória Imunológica , Interleucina-15/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CCR5/genética , Doença Aguda , Adulto , Animais , Morte Celular/genética , Proliferação de Células/genética , Feminino , Hepatite A/complicações , Hepatite A/genética , Hepatite A/imunologia , Humanos , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptores CCR5/metabolismo , Receptores CCR7/metabolismo , Regulação para Cima/genética , Adulto Jovem
10.
Cell Mol Immunol ; 18(2): 385-397, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32332901

RESUMO

Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8+ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8+ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8+ T cells (CD8+ TILs) obtained from non-small-cell lung cancer patients. Single-cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8+ TILs. Furthermore, we found that human CD28+CD8+ but not CD28-CD8+ TILs responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 costimulation in human CD8+ TILs is dispensable for PD-1 blockade-induced reinvigoration and that loss of CD28 expression serves as a marker of anti-PD-1 antibody-unresponsive CD8+ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28-PD-1+CD8+ TILs exhibited characteristics of terminally exhausted CD8+ T cells with low TCF1 expression. Notably, CD28-PD-1+CD8+ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced the proliferation of CD28-PD-1+CD8+ TILs as well as CD28+PD-1+CD8+ TILs. Taken together, these results show that loss of CD28 expression is a marker of PD-1 blockade-unresponsive human CD8+ TILs with a TCF1- signature and provide mechanistic insights into combining IL-15 with anti-PD-1 antibodies.


Assuntos
Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Interleucina-15/metabolismo , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL
11.
Cancer Lett ; 499: 137-147, 2021 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-33249194

RESUMO

Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8+ tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8+ TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer. We also evaluated the reinvigoration of exhausted CD8+ TILs upon ex vivo treatment with inhibitory checkpoint blockers. TOX-expressing PD-1highCD8+ TILs had the highest expression of immune checkpoint receptors (ICRs), the most terminally exhausted features, and the highest tumor antigen reactivity among PD-1+CD8+ TILs. Bladder cancer patients with a high percentage of PD-1highTOX+CD8+ TILs had more progressed T-cell exhaustion features and higher programmed death-ligand 1 expression in tumor tissues. TIGIT was the most frequent co-expressed ICR on PD-1+CD8+ TILs, and TIGIT blockade enhanced the PD-1 blockade-mediated cytokine production by CD8+ TILs from bladder cancer patients. Our findings provide an improved understanding of the heterogeneous exhaustion status of CD8+ TILs and additional immunotherapy strategies to improve outcomes of bladder cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células de Transição/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores Imunológicos/antagonistas & inibidores , Neoplasias da Bexiga Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/patologia , Quimioterapia Adjuvante/métodos , Cistectomia , Sinergismo Farmacológico , Feminino , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , Receptores Imunológicos/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
12.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34230109

RESUMO

BACKGROUND: Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells. METHODS: To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling. RESULTS: Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys. CONCLUSION: The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Animais , Anticorpos Biespecíficos/farmacologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Camundongos
13.
Immune Netw ; 20(1): e3, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32158591

RESUMO

Immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 therapeutic agents, are now approved by the Food and Drug Administration for treatment of various types of cancer. However, the therapeutic efficacy of ICIs varies among patients and cancer types. Moreover, most patients do not develop durable antitumor responses after ICI therapy due to an ephemeral reversal of T-cell dysfunction. As co-stimulatory receptors play key roles in regulating the effector functions of T cells, activating co-stimulatory pathways may improve checkpoint inhibition efficacy, and lead to durable antitumor responses. Here, we review recent advances in our understating of co-stimulatory receptors in cancers, providing the necessary groundwork for the rational design of cancer immunotherapy.

14.
Dis Model Mech ; 11(7)2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-29967068

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice, in which HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared with wild-type (WT) mice. These parameters were restored to, if not better than, the WT levels when we examined hMRP8 Hif-1a KO mice upon 5% DSS feeding. hMRP8 Hif-2a KO mice, on the other hand, exhibited a similar degree of DSS-induced colitis to that of WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1a KO mice exhibited comparable levels of colorectal tumors to those of WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1α activation in myeloid cells critically regulates IBD progression.


Assuntos
Colite/induzido quimicamente , Colite/patologia , Progressão da Doença , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células Mieloides/metabolismo , Células Mieloides/patologia , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Antígenos Ly/metabolismo , Azoximetano , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Antígeno CD11b/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Colite/metabolismo , Colite/prevenção & controle , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana , Suscetibilidade a Doenças , Humanos , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
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