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1.
Nat Immunol ; 24(10): 1645-1653, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37709986

RESUMO

Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8+ T cells in the context of chronic infections and tumors but was selectively required in tumor-induced CD8+ T cell exhaustion. Overexpression of NFAT5 in CD8+ T cells reduced tumor control, while deletion of NFAT5 improved tumor control by promoting the accumulation of tumor-specific CD8+ T cells that had reduced expression of the exhaustion-associated proteins TOX and PD-1 and produced more cytokines, such as IFNÉ£ and TNF, than cells with wild-type levels of NFAT5, specifically in the precursor exhausted PD-1+TCF1+TIM-3-CD8+ T cell population. NFAT5 did not promote T cell exhaustion during chronic infection with clone 13 of lymphocytic choriomeningitis virus. Expression of NFAT5 was induced by TCR triggering, but its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. Thus, NFAT5 promoted the exhaustion of CD8+ T cells in a tumor-selective fashion.


Assuntos
Coriomeningite Linfocítica , Neoplasias , Humanos , Fatores de Transcrição/metabolismo , Linfócitos T CD8-Positivos , Exaustão das Células T , Infecção Persistente , Microambiente Tumoral , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Vírus da Coriomeningite Linfocítica , Neoplasias/metabolismo
2.
Nature ; 629(8011): 426-434, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38658764

RESUMO

Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rß-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.


Assuntos
Linfócitos T CD8-Positivos , Proliferação de Células , Dinoprostona , Interleucina-2 , Linfócitos do Interstício Tumoral , Mitocôndrias , Transdução de Sinais , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Dinoprostona/metabolismo , Regulação para Baixo , Ferroptose , Subunidade gama Comum de Receptores de Interleucina/biossíntese , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Interleucina-2/antagonistas & inibidores , Interleucina-2/imunologia , Interleucina-2/metabolismo , Subunidade beta de Receptor de Interleucina-2/metabolismo , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/imunologia
3.
EMBO J ; 41(12): e109300, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35467036

RESUMO

Group-2 innate lymphoid cells (ILC2s), which are involved in type 2 inflammatory diseases such as allergy, can exhibit immunological memory, but the basis of this ILC2 "trained immunity" has remained unclear. Here, we found that stimulation with IL-33/IL-25 or exposure to the allergen papain induces the expression of the transcription factor c-Maf in mouse ILC2s. Chronic papain exposure results in high production of IL-5 and IL-13 cytokines and lung eosinophil recruitment, effects that are blocked by c-Maf deletion in ILCs. Transcriptomic analysis revealed that knockdown of c-Maf in ILC2s suppresses expression of type 2 cytokine genes, as well as of genes linked to a memory-like phenotype. Consistently, c-Maf was found highly expressed in human adult ILC2s but absent in cord blood and required for cytokine production in isolated human ILC2s. Furthermore, c-Maf-deficient mouse or human ILC2s failed to exhibit strengthened ("trained") responses upon repeated challenge. Thus, the expression of c-Maf is indispensable for optimal type 2 cytokine production and proper memory-like responses in group-2 innate lymphoid cells.


Assuntos
Imunidade Inata , Linfócitos , Animais , Citocinas/metabolismo , Humanos , Interleucina-33/genética , Interleucina-33/metabolismo , Pulmão/metabolismo , Linfócitos/metabolismo , Camundongos , Papaína/metabolismo , Proteínas Proto-Oncogênicas c-maf/metabolismo
4.
Gut ; 71(3): 457-466, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34253574

RESUMO

OBJECTIVE: In this study, we determined whether Helicobacter pylori (H. pylori) infection dampens the efficacy of cancer immunotherapies. DESIGN: Using mouse models, we evaluated whether immune checkpoint inhibitors or vaccine-based immunotherapies are effective in reducing tumour volumes of H. pylori-infected mice. In humans, we evaluated the correlation between H. pylori seropositivity and the efficacy of the programmed cell death protein 1 (PD-1) blockade therapy in patients with non-small-cell lung cancer (NSCLC). RESULTS: In mice engrafted with MC38 colon adenocarcinoma or B16-OVA melanoma cells, the tumour volumes of non-infected mice undergoing anticytotoxic T-lymphocyte-associated protein 4 and/or programmed death ligand 1 or anti-cancer vaccine treatments were significantly smaller than those of infected mice. We observed a decreased number and activation status of tumour-specific CD8+ T cells in the tumours of infected mice treated with cancer immunotherapies independent of the gut microbiome composition. Additionally, by performing an in vitro co-culture assay, we observed that dendritic cells of infected mice promote lower tumour-specific CD8+ T cell proliferation. We performed retrospective human clinical studies in two independent cohorts. In the Dijon cohort, H. pylori seropositivity was found to be associated with a decreased NSCLC patient survival on anti-PD-1 therapy. The survival median for H. pylori seropositive patients was 6.7 months compared with 15.4 months for seronegative patients (p=0.001). Additionally, in the Montreal cohort, H. pylori seropositivity was found to be associated with an apparent decrease of NSCLC patient progression-free survival on anti-PD-1 therapy. CONCLUSION: Our study unveils for the first time that the stomach microbiota affects the response to cancer immunotherapies and that H. pylori serology would be a powerful tool to personalize cancer immunotherapy treatment.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Infecções por Helicobacter/complicações , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Animais , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Helicobacter pylori , Humanos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estudos Retrospectivos
5.
Eur J Immunol ; 50(4): 505-514, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31785153

RESUMO

It is known that for achieving high affinity antibody responses, vaccines must be optimized for antigen dose/density, and the prime/boost interval should be at least 4 weeks. Similar knowledge is lacking for generating high avidity T-cell responses. The functional avidity (FA) of T cells, describing responsiveness to peptide, is associated with the quality of effector function and the protective capacity in vivo. Despite its importance, the FA is rarely determined in T-cell vaccination studies. We addressed the question whether different time intervals for short-term homologous vaccinations impact the FA of CD8 T-cell responses. Four-week instead of 2-week intervals between priming and boosting with potent subunit vaccines in C57BL/6 mice did not improve FA. Equally, similar FA was observed after vaccination with virus-like particles displaying low versus high antigen densities. Interestingly, FA was stable in vivo but not in vitro, depending on the antigen dose and the time interval since T-cell activation, as observed in murine monoclonal T cells. Our findings suggest dynamic in vivo modulation for equal FA. We conclude that low antigen density vaccines or a minimal 4-week prime/boost interval are not crucial for the T-cell's FA, in contrast to antibody responses.


Assuntos
Antígenos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Formação de Anticorpos , Apresentação de Antígeno , Antígenos/imunologia , Células Cultivadas , Imunização Secundária , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/imunologia , Ligação Proteica , Vacinação
6.
EMBO J ; 34(15): 2042-58, 2015 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-26139534

RESUMO

T cells infiltrating neoplasms express surface molecules typical of chronically virus-stimulated T cells, often termed "exhausted" T cells. We compared the transcriptome of "exhausted" CD8 T cells infiltrating autochthonous melanomas to those of naïve and acutely stimulated CD8 T cells. Despite strong similarities between transcriptional signatures of tumor- and virus-induced exhausted CD8 T cells, notable differences appeared. Among transcriptional regulators, Nr4a2 and Maf were highly overexpressed in tumor-exhausted T cells and significantly upregulated in CD8 T cells from human melanoma metastases. Transduction of murine tumor-specific CD8 T cells to express Maf partially reproduced the transcriptional program associated with tumor-induced exhaustion. Upon adoptive transfer, the transduced cells showed normal homeostasis but failed to accumulate in tumor-bearing hosts and developed defective anti-tumor effector responses. We further identified TGFß and IL-6 as main inducers of Maf expression in CD8 T cells and showed that Maf-deleted tumor-specific CD8 T cells were much more potent to restrain tumor growth in vivo. Therefore, the melanoma microenvironment contributes to skewing of CD8 T cell differentiation programs, in part by TGFß/IL-6-mediated induction of Maf.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Melanoma/metabolismo , Proteínas Proto-Oncogênicas c-maf/metabolismo , Microambiente Tumoral/fisiologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Primers do DNA/genética , Citometria de Fluxo , Perfilação da Expressão Gênica , Proteínas de Homeodomínio/genética , Interleucina-6/metabolismo , Luciferases , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-maf/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/metabolismo
7.
J Immunol ; 199(8): 2713-2720, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28864471

RESUMO

Peripheral tolerance mechanisms exist to prevent autoimmune destruction by self-reactive T cells that escape thymic deletion. Dominant tolerance imposed by CD4+Foxp3+ T regulatory cells can actively control autoaggressive T cell responses. Tolerance mechanisms that act endogenous to the T cell also exist. These mechanisms include T cell inactivation (anergy) and deletion. A major difference between anergic T cells and T cells undergoing peripheral deletion is the capacity of the latter to still signal through MAPKs upon TCR stimulation, suggesting these signals may be required for T deletion. In this study, we used several different models of CD8 T cell deletion to investigate the contribution of MAPK activation. Using chemical inhibitors, we established that inhibition of p38, but not ERK or JNK, rescue T cells from undergoing peripheral deletion both in vitro and in vivo. Using T cell-specific murine lines genetically altered in expression of p38α, and mice in which p38α was deleted only in CD11c-expressing cells, we surprisingly found that CD8 T cell-intrinsic p38α activation was not responsible for increased survival, but rather that inhibition of p38α in the Ag-presenting dendritic cells prevented CD8 T cell deletion.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Deleção Clonal , Células Dendríticas/imunologia , Tolerância Periférica , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antígeno CD11c/metabolismo , Linhagem Celular , Apresentação Cruzada , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética
8.
Biochim Biophys Acta ; 1865(1): 49-57, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26123831

RESUMO

The immune system has the potential to protect from malignant diseases for extended periods of time. Unfortunately, spontaneous immune responses are often inefficient. Significant effort is required to develop reliable, broadly applicable immunotherapies for cancer patients. A major innovation was transplantation with hematopoietic stem cells from genetically distinct donors for patients with hematologic malignancies. In this setting, donor T cells induce long-term remission by keeping cancer cells in check through powerful allogeneic graft-versus-leukemia effects. More recently, a long awaited breakthrough for patients with solid tissue cancers was achieved, by means of therapeutic blockade of T cell inhibitory receptors. In untreated cancer patients, T cells are dysfunctional and remain in a state of T cell "exhaustion". Nonetheless, they often retain a high potential for successful defense against cancer, indicating that many T cells are not entirely and irreversibly exhausted but can be mobilized to become highly functional. Novel antibody therapies that block inhibitory receptors can lead to strong activation of anti-tumor T cells, mediating clinically significant anti-cancer immunity for many years. Here we review these new treatments and the current knowledge on tumor antigen-specific T cells.


Assuntos
Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Humanos , Imunoterapia , Neoplasias/terapia , Transdução de Sinais , Transcrição Gênica
9.
Immunology ; 150(2): 199-212, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27716898

RESUMO

Cancer-germline genes in both humans and mice have been shown to encode antigens susceptible to targeting by cytotoxic CD8 T effector cells (CTL). We analysed the ability of CTL to kill different tumour cell lines expressing the same cancer-germline gene P1A (Trap1a). We previously demonstrated that CTL expressing a T-cell receptor specific for the P1A35-43 peptide associated with H-2Ld , although able to induce regression of P1A-expressing P815 mastocytoma cells, were much less effective against P1A-expressing melanoma cells. Here, we analysed parameters of the in vitro interaction between P1A-specific CTL and mastocytoma or melanoma cells expressing similar levels of the P1A gene and of surface H-2Ld . The mastocytoma cells were more sensitive to cytolysis than the melanoma cells in vitro. Analysis by video-microscopy of early events required for target cell killing showed that similar patterns of increase in cytoplasmic Ca2+ concentration ([Ca2+ ]i) were induced by both types of P1A-expressing tumour cells. However, the use of CTL expressing a fluorescent granzyme B (GZMB-Tom) showed a delay in the migration of cytotoxic granules to the tumour interaction site, as well as a partially deficient GZMB-Tom exocytosis in response to the melanoma cells. Among surface molecules possibly affecting tumour-CTL interactions, the mastocytoma cells were found to express intercellular adhesion molecule-1, the ligand for LFA-1, which was not detected on the melanoma cells.


Assuntos
Antígenos de Neoplasias/metabolismo , Exocitose , Mastocitoma/imunologia , Melanoma/imunologia , Fragmentos de Peptídeos/metabolismo , Vesículas Secretórias/metabolismo , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos de Neoplasias/genética , Sinalização do Cálcio , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Antígeno de Histocompatibilidade H-2D/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Ativação Linfocitária , Antígeno-1 Associado à Função Linfocitária/metabolismo , Camundongos , Especificidade do Receptor de Antígeno de Linfócitos T
10.
Proc Natl Acad Sci U S A ; 111(30): 11115-20, 2014 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-25024217

RESUMO

The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Cisteína Endopeptidases/imunologia , Imunidade Celular , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Melanoma/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/patologia , Cisteína Endopeptidases/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
J Immunol ; 193(7): 3409-16, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25156361

RESUMO

Peripheral tolerance mechanisms are in place to prevent T cells from mediating aberrant immune responses directed against self and environmental Ags. Mechanisms involved in the induction of peripheral tolerance include T cell-intrinsic pathways, such as anergy or deletion, or exogenous tolerance mediated by regulatory T cells. We have previously shown that the density of peptide-MHC class I recognized by the TCR determines whether CD8(+) T cells undergo anergy or deletion. Specifically, using a TCR-transgenic CD8(+) T cell model, we demonstrated that persistent peripheral exposure to low- or high-dose peptides in the absence of inflammatory signals resulted in clonal deletion or anergy of the T cell, respectively. In this study, by altering the affinity of the peptide-MHC tolerogen for TCR, we have confirmed that this mechanism is dependent on the level of TCR signaling that the CD8(+) T cell receives. Using altered peptide ligands (APLs) displaying high TCR affinities, we show that increasing the TCR signaling favors anergy induction. Conversely, using APLs displaying a decreased TCR affinity tilted our system in the direction of deletional tolerance. We demonstrate how differential peripheral CD8(+) T cell tolerance mechanisms are controlled by both the potency and density of MHC class I-peptide tolerogen.


Assuntos
Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Tolerância Imunológica/fisiologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígenos/genética , Linfócitos T CD8-Positivos/citologia , Antígenos de Histocompatibilidade Classe I/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Peptídeos/genética , Receptores de Antígenos de Linfócitos T/genética
12.
J Immunol ; 191(7): 3712-24, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24006458

RESUMO

In adoptive therapy, CD8 T cells expressing active STAT5 (STAT5CA) transcription factors were found to be superior to unmanipulated counterparts in long-term persistence, capacity to infiltrate autochthonous mouse melanomas, thrive in their microenvironment, and induce their regression. However, the molecular mechanisms sustaining these properties were undefined. In this study, we report that STAT5CA induced sustained expression of genes controlling tissue homing, cytolytic granule composition, type 1 CD8 cytotoxic T cell-associated effector molecules granzyme B(+), IFN-γ(+), TNF-α(+), and CCL3(+), but not IL-2, and transcription factors T-bet and eomesodermin (Eomes). Chromatin immunoprecipitation sequencing analyses identified the genes possessing regulatory regions to which STAT5 bound in long-term in vivo maintained STAT5CA-expressing CD8 T cells. This analysis identified 34% of the genes differentially expressed between STAT5CA-expressing and nonexpressing effector T cells as direct STAT5CA target genes, including those encoding T-bet, Eomes, and granzyme B. Additionally, genes encoding the IL-6R and TGFbRII subunits were stably repressed, resulting in dampened IL-17-producing CD8 T cell polarization in response to IL-6 and TGF-ß1. The absence of T-bet did not affect STAT5CA-driven accumulation of the T cells in tissue or their granzyme B expression but restored IL-2 secretion and IL-6R and TGFbRII expression and signaling, as illustrated by IL-17 induction. Therefore, concerted STAT5/T-bet/Eomes regulation controls homing, long-term maintenance, recall responses, and resistance to polarization towards IL-17-producing CD8 T cells while maintaining expression of an efficient type 1 CD8 cytotoxic T cell program (granzyme B(+), IFN-γ(+)).


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Interleucina-6/metabolismo , Fator de Transcrição STAT5/metabolismo , Proteínas com Domínio T/genética , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Interleucina-17/metabolismo , Camundongos , Camundongos Transgênicos , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT5/genética , Transdução de Sinais , Proteínas com Domínio T/deficiência , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Transcrição Gênica
13.
Cancers (Basel) ; 16(12)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38927950

RESUMO

Bladder cancer (BC) is the fourth most common cancer in men, with a poor patient prognosis for advanced disease. The poor survival of patients with muscle-invasive bladder cancer (MIBC) and metastatic status emphasizes the urgent need to develop new therapies. Lacking in the field of BC is the availability of relevant advanced BC mouse models, especially metastatic ones, that accurately recapitulate the complexities of human pathology to test and study new therapeutic strategies. Addressing this need, we developed a traceable mouse model of BC that expresses tumor-associated antigens within the context of advanced muscle-invasive BC. This novel system was achieved through the deletion of the tp53 and pten genes, alongside the incorporation of the fusion construct of Firefly luciferase (Luc) and the SIYRYYGL (SIY) T-cell antigen. We validate that the presence of the transgene did not impact on the development of the tumors while allowing us to measure tumor progression by bioluminescence. We show that the transgene did not influence the composition of the immune tumor microenvironment. More importantly, we report that this model was unresponsive to anti-PD-1 treatment, as in the majority of patients with BC. We also develop a new model based on the orthotopic injection of BC clonal cell lines derived from our first model. We demonstrate that this new model invades the muscle layer and has a metastasis development rate of 83%. The advantage of this model is that we can visualize tumor growth and metastasis development in vivo. These mouse models' characteristics, displaying many similarities with the human pathology, provide a valuable tool for tracking tumor progression, metastasis spread in vivo, and treatment resistance, as well as exploring fundamental and translational aspects of BC biology. This work contributes to the improvement in the landscape of mouse models of advanced BC for testing new therapeutic strategies.

14.
Cancers (Basel) ; 16(2)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38275874

RESUMO

Blood-based biomarkers represent ideal candidates for the development of non-invasive immuno-oncology-based assays. However, to date, no blood biomarker has been validated to predict clinical responses to immunotherapy. In this study, we used next-generation sequencing (RNAseq) on bulk RNA extracted from whole blood and tumor samples in a pre-clinical MIBC mouse model. We aimed to identify biomarkers associated with immunotherapy response and assess the potential application of simple non-invasive blood biomarkers as a therapeutic decision-making assay compared to tissue-based biomarkers. We established that circulating immune cells and the tumor microenvironment (TME) display highly organ-specific transcriptional responses to ICIs. Interestingly, in both, a common lymphocytic activation signature can be identified associated with the efficient response to immunotherapy, including a blood-specific CD8+ T cell activation/proliferation signature which predicts the immunotherapy response.

15.
J Exp Med ; 219(12)2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36121415

RESUMO

Small intestinal villi are structural and functional units present in higher vertebrates and uniquely adapted to nutrient absorption. Villus enterocytes are organized in transcriptional "zones" dedicated to specialized tasks such as absorption of specific nutrients. We report that the transcription factor c-MAF is expressed in differentiated lower and mid-villus enterocytes and is a target of BMP signaling. Maf inactivation perturbed the villus zonation program by increasing carbohydrate-related transcripts while suppressing transcripts linked to amino-acid and lipid absorption. The formation of cytoplasmic lipid droplets, shuttling dietary fat to chylomicrons, was impaired upon Maf loss indicating its role in dietary lipid handling. Maf inactivation under homeostatic conditions expanded tuft cells and led to compensatory gut lengthening, preventing weight loss. However, delayed Maf-/- enterocyte maturation impaired weight recovery after acute intestinal injury, resulting in reduced survival. Our results identify c-MAF as a regulator of the intestinal villus zonation program, while highlighting the importance of coordination between stem/progenitor and differentiation programs for intestinal regeneration.


Assuntos
Quilomícrons , Enterócitos , Animais , Carboidratos , Gorduras na Dieta , Nutrientes , Fatores de Transcrição
16.
Proc Natl Acad Sci U S A ; 105(43): 16683-8, 2008 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-18936481

RESUMO

Because of mechanisms of self-tolerance, many tumor-specific CD8 T cells exhibit low avidity for tumor antigens and would benefit from strategies that enhance their numbers and effector function. Here we demonstrate that the combined use of two different types of immune adjuvants, one that directly targets the CD8 cell, IL-2/anti-IL-2 mAb complexes, and one that targets the innate immune system, poly(I:C), can achieve this goal. Provision of IL-2/mAb complexes was found to enhance the activation and effector function of low-avidity tumor-specific T cells, yet this was insufficient to achieve tumor eradication. The addition of poly(I:C) further increased the accumulation of granzyme B-expressing effectors within the tumor and resulted in tumor eradication. This strategy presents many of the benefits of whole-body irradiation, including the provision of high levels of homeostatic cytokines, enhanced expansion of effector cells relative to regulatory T cells, and provision of inflammatory cytokines, and is therefore likely to serve as a strategy for both tumor vaccines and adoptive immunotherapy of cancer.


Assuntos
Adjuvantes Imunológicos/farmacologia , Imunidade/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias/terapia , Animais , Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/química , Citocinas , Imunoterapia Adotiva/métodos , Interleucina-2/imunologia , Camundongos , Camundongos Transgênicos , Poli I-C/uso terapêutico , Resultado do Tratamento
17.
Cancers (Basel) ; 13(18)2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34572939

RESUMO

Tumor-associated macrophages (TAMs) are one of the most abundant infiltrating immune cells of solid tumors. Despite their possible dual role, i.e., pro- or anti-tumoral, there is considerable evidence showing that the accumulation of TAMs promotes tumor progression rather than slowing it. Several strategies are being developed and clinically tested to target these cells. Bladder cancer (BCa) is one of the most common cancers, and despite heavy treatments, including immune checkpoint inhibitors (ICIs), the overall patient survival for advanced BCa is still poor. TAMs are present in bladder tumors and play a significant role in BCa development. However, few investigations have analyzed the effect of targeting TAMs in BCa. In this review, we focus on the importance of TAMs in a cancerous bladder, their association with patient outcome and treatment efficiency as well as on how current BCa treatments impact these cells. We also report different strategies used in other cancer types to develop new immunotherapeutic strategies with the aim of improving BCa management through TAMs targeting.

18.
Oncoimmunology ; 10(1): 1873585, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33643691

RESUMO

The understanding of the role of B cells in patients with solid tumors remains insufficient. We found that circulating B cells produced TNFα and/or IL-6, associated with unresponsiveness and poor overall survival of melanoma patients treated with anti-CTLA4 antibody. Transcriptome analysis of B cells from melanoma metastases showed enriched expression of inflammatory response genes. Publicly available single B cell data from the tumor microenvironment revealed a negative correlation between TNFα expression and response to immune checkpoint blockade. These findings suggest that B cells contribute to tumor growth via the production of inflammatory cytokines. Possibly, these B cells are different from tertiary lymphoid structure-associated B cells, which have been described to correlate with favorable clinical outcome of cancer patients. Further studies are required to identify and characterize B cell subsets and their functions promoting or counteracting tumor growth, with the aim to identify biomarkers and novel treatment targets.


Assuntos
Melanoma , Estruturas Linfoides Terciárias , Linfócitos B , Perfilação da Expressão Gênica , Humanos , Melanoma/tratamento farmacológico , Microambiente Tumoral
19.
Front Immunol ; 11: 206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32117317

RESUMO

Beyond its well-admitted role in development and organogenesis, it is now clear that the transcription factor c-Maf has owned its place in the realm of immune-related transcription factors. Formerly introduced solely as a Th2 transcription factor, the role attributed to c-Maf has gradually broadened over the years and has extended to most, if not all, known immune cell types. The influence of c-Maf is particularly prominent among T cell subsets, where c-Maf regulates the differentiation as well as the function of multiple subsets of CD4 and CD8 T cells, lending it a crucial position in adaptive immunity and anti-tumoral responsiveness. Recent research has also revealed the role of c-Maf in controlling Th17 responses in the intestine, positioning it as an essential factor in intestinal homeostasis. This review aims to present and discuss the recent advances highlighting the particular role played by c-Maf in T lymphocyte differentiation, function, and homeostasis.


Assuntos
Tolerância Imunológica , Proteínas Proto-Oncogênicas c-maf/fisiologia , Linfócitos T/imunologia , Diferenciação Celular , Humanos , Interleucina-10/biossíntese , Intestinos/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/análise , Proteínas Proto-Oncogênicas c-maf/genética , Linfócitos T/citologia , Linfócitos T/fisiologia
20.
Oncoimmunology ; 9(1): 1736792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850194

RESUMO

Despite the success of immunotherapy using checkpoint blockade, many patients with solid tumors remain refractory to these treatments. In human cancer, the experimental options to investigate the specific effects of antibodies blocking inhibitory receptors are limited and it is still unclear which cell types are involved. We addressed the question whether the direct interaction between T cells and tumor cells can be enforced through blocking a set of inhibitory receptors including PD-1, TIM-3, BTLA and LAG-3, blocked either individually or in dual combinations with the anti-PD-1 antibody, and to determine the condition that induces maximal T cell function preventing tumor cell proliferation. Using short-term Melan-A-specific or autologous re-stimulations, checkpoint blockade did not consistently increase cytokine production by tumor-derived expanded T cells. We next set up a 5-day co-culture assay with autologous melanoma cell lines and expanded tumor infiltrating T cells, originating from tumor specimens obtained from 6 different patients. Amongst all combos tested, we observed that blockade of LAG-3 alone, and more strongly when combined with PD-1 blockade, enforced T cell responses and tumor cell growth control. The combination of anti-LAG-3 plus anti-PD-1 acted through CD8 T cells and led to increased IFNγ production and cytotoxic capacity. Our results show that LAG-3 and PD-1 are regulating the direct interaction between tumor cells and autologous T cells, suggesting that therapy effects may be promoted by enhanced access of the corresponding blocking reagents to the tumor microenvironment.


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Técnicas de Cocultura , Humanos , Imunoterapia , Ativação Linfocitária , Melanoma/tratamento farmacológico , Microambiente Tumoral
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