RESUMEN
CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Ratones , Animales , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Diferenciación Celular , Proliferación Celular , Receptores de Antígenos de Linfocitos TRESUMEN
The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NFï«B and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients' clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.
RESUMEN
The T cell receptor (TCR) endows T cells with antigen specificity and is central to nearly all aspects of T cell function. Each naïve T cell has a unique TCR sequence that is stably maintained during cell division. In this way, the TCR serves as a molecular barcode that tracks processes such as migration, differentiation, and proliferation of T cells. Recent technological advances have enabled sequencing of the TCR from single cells alongside deep molecular phenotypes on an unprecedented scale. In this review, we discuss strengths and limitations of TCR sequences as molecular barcodes and their application to study immune responses following Programmed Death-1 (PD-1) blockade in cancer. Additionally, we consider applications of TCR data beyond use as a barcode.
Asunto(s)
Autoinmunidad , Neoplasias , Autoinmunidad/genética , Humanos , Neoplasias/genética , Receptores de Antígenos de Linfocitos T/genética , Linfocitos TRESUMEN
PURPOSE OF REVIEW: Immunotherapies such as immune checkpoint blockade have revolutionized cancer treatment, but current approaches have failed to improve outcomes in glioblastoma and other brain tumours. T cell dysfunction has emerged as one of the major barriers for the development of central nervous system (CNS)-directed immunotherapy. Here, we explore the unique requirements that T cells must fulfil to ensure immune surveillance in the CNS, and we analyse T cell dysfunction in glioblastoma (GBM) through the prism of CNS-resident immune responses. RECENT FINDINGS: Using comprehensive and unbiased techniques such as single-cell RNA sequencing, multiple studies have dissected the transcriptional state of CNS-resident T cells that patrol the homeostatic brain. A similar approach has revealed that in GBM, tumour-infiltrating T cells lack the hallmarks of antigen-driven exhaustion typical of melanoma and other solid tumours, suggesting the need for better presentation of tumour-derived antigens. Consistently, in a mouse model of GBM, increasing lymphatic drainage to the cervical lymph node was sufficient to promote tumour rejection. SUMMARY: For the success of future immunotherapy strategies, further work needs to explore the natural history of dysfunction in GBM tumour-infiltrating T cells, establish whether these originate from CNS-resident T cells and how they can be manipulated therapeutically.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Animales , Neoplasias Encefálicas/terapia , Sistema Nervioso Central , Glioblastoma/terapia , Humanos , Inmunoterapia , Ratones , Linfocitos TRESUMEN
The introduction of immunotherapy with checkpoint receptor blockade has changed the treatment of advanced cancers, at times inducing prolonged remission. Nevertheless, the success rate of the approach is variable across patients and different tumor types, and treatment is often accompanied by severe immune-related side effects, suggesting the importance of co-inhibitory pathway for both prevention of autoimmunity and failure of tumor rejection. A better understanding of how to uncouple anti-tumor activity from loss of self-tolerance is necessary to increase the therapeutic efficacy of checkpoint immunotherapy. In this review, we describe basic concepts of T-cell exhaustion that occur in cancer, highlighting the role of co-inhibitory receptors in contributing to this process while preventing immunopathology. By providing an overview of the current therapeutic success and immune-related burden of secondary effects of checkpoint immunotherapy, we illustrate the "double-edged sword" related to interference with immune-regulatory pathways. Finally, since achieving tumor rejection while preserving self-tolerance is particularly important for the central nervous system, we analyze the case for checkpoint immunotherapy in glioblastoma, the most common adult brain tumor.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias Encefálicas/terapia , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Glioblastoma/terapia , Inmunoterapia/métodos , Autotolerancia , Linfocitos T/inmunología , Adulto , Animales , Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Humanos , Terapia de Inmunosupresión , Escape del TumorRESUMEN
The genetic predisposition to multiple sclerosis (MS) is most strongly conveyed by MHC class II haplotypes, possibly by shaping the autoimmune CD4 T cell repertoire. Whether Ag-processing enzymes contribute to MS susceptibility by editing the peptide repertoire presented by these MHC haplotypes is unclear. Thymus-specific serine protease (TSSP) is expressed by thymic epithelial cells and thymic dendritic cells (DCs) and, in these two stromal compartments, TSSP edits the peptide repertoire presented by class II molecules. We show in this article that TSSP increases experimental autoimmune encephalomyelitis severity by limiting central tolerance to myelin oligodendrocyte glycoprotein. The effect on experimental autoimmune encephalomyelitis severity was MHC class II allele dependent, because the lack of TSSP expression conferred protection in NOD mice but not in C57BL/6 mice. Importantly, although human thymic DCs express TSSP, individuals segregate into two groups having a high or 10-fold lower level of expression. Therefore, the level of TSSP expression by thymic DCs may modify the risk factors for MS conferred by some MHC class II haplotypes.
Asunto(s)
Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Células Epiteliales/inmunología , Esclerosis Múltiple/inmunología , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Timo/metabolismo , Adolescente , Animales , Células Cultivadas , Tolerancia Central , Niño , Preescolar , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Glicoproteína Mielina-Oligodendrócito/inmunologíaRESUMEN
T-cell polyspecificity, predicting that individual T cells recognize a continuum of related ligands, implies that multiple antigens can tolerize T cells specific for a given self-antigen. We previously showed in C57BL/6 mice that part of the CD4(+) T-cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35-55 also recognizes the neuronal antigen neurofilament medium (NF-M) 15-35. Such bi-specific CD4(+) T cells are frequent and produce inflammatory cytokines after stimulation. Since T cells recognizing two self-antigens would be expected to be tolerized more efficiently, this finding prompted us to study how polyspecificity impacts tolerance. We found that similar to MOG, NF-M is expressed in the thymus by medullary thymic epithelial cells, a tolerogenic population. Nevertheless, the frequency, phenotype, and capacity to transfer experimental autoimmune encephalomyelitis (EAE) of MOG35-55 -reactive CD4(+) T cells were increased in MOG-deficient but not in NF-M-deficient mice. We found that presentation of NF-M15-35 by I-A(b) on dendritic cells is of short duration, suggesting unstable MHC class II binding. Consistently, introducing an MHC-anchoring residue into NF-M15-35 (NF-M15-35 T20Y) increased its immunogenicity, activating a repertoire able to induce EAE. Our results show that in C57BL/6 mice bi-specific encephalitogenic T cells manage to escape tolerization due to inefficient exposure to two self-antigens.
Asunto(s)
Autoantígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Tolerancia Inmunológica , Proteínas de la Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuronas/inmunología , Animales , Citocinas/biosíntesis , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Expresión Génica , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Glicoproteína Mielina-Oligodendrócito/genética , Proteínas de Neurofilamentos/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/genética , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Timo/inmunología , Timo/metabolismoRESUMEN
Polyspecific T cells recognizing multiple distinct self-antigens have been identified in multiple sclerosis and other organ-specific autoimmune diseases, but their pathophysiological relevance remains undetermined. Using a mouse model of multiple sclerosis, we show that autoimmune encephalomyelitis induction is strictly dependent on reactivation of pathogenic T cells by a peptide (35-55) derived from myelin oligodendrocyte glycoprotein (MOG). This disease-inducing response wanes after onset. Strikingly, the progression of disease is driven by the in situ activation and expansion of a minority of MOG35-55-specific T cells that also recognize neurofilament-medium (NF-M)15-35, an intermediate filament protein expressed in neurons. This mobilization of bispecific T cells is critical for disease progression as adoptive transfer of NF-M15-35/MOG35-55 bispecific T cell lines caused full-blown disease in wild-type but not NF-M-deficient recipients. Moreover, specific tolerance through injection of NF-M15-35 peptide at the peak of disease halted experimental autoimmune encephalomyelitis progression. Our findings highlight the importance of polyspecific autoreactive T cells in the aggravation and perpetuation of central nervous system autoimmunity.
Asunto(s)
Autoantígenos/inmunología , Autoinmunidad , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Linfocitos T/inmunología , Animales , Células Cultivadas , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Noqueados , Fragmentos de Péptidos/inmunologíaRESUMEN
The recognition of multiple ligands by a single TCR is an intrinsic feature of T cell biology, with important consequences for physiological and pathological processes. Polyspecific T cells targeting distinct self-antigens have been identified in healthy individuals as well as in the context of autoimmunity. We have previously shown that the 2D2 TCR recognizes the myelin oligodendrocyte glycoprotein epitope (MOG)35-55 as well as an epitope within the axonal protein neurofilament medium (NF-M15-35) in H-2(b) mice. In this study, we assess whether this cross-reactivity is a common feature of the MOG35-55-specific T cell response. To this end, we analyzed the CD4 T cell response of MOG35-55-immunized C57BL/6 mice for cross-reactivity with NF-M15-35. Using Ag recall responses, we established that an important proportion of MOG35-55-specific CD4 T cells also responded to NF-M15-35 in all mice tested. To study the clonality of this response, we analyzed 22 MOG35-55-specific T cell hybridomas expressing distinct TCR. Seven hybridomas were found to cross-react with NF-M15-35. Using an alanine scan of NF-M18-30 and an in silico predictive model, we dissected the molecular basis of cross-reactivity between MOG35-55 and NF-M15-35. We established that NF-M F24, R26, and V27 proved important TCR contacts. Strikingly, the identified TCR contacts are conserved within MOG38-50. Our data indicate that due to linear sequence homology, part of the MOG35-55-specific T cell repertoire of all C57BL/6 mice also recognizes NF-M15-35, with potential implications for CNS autoimmunity.
Asunto(s)
Autoantígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Vaina de Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Proteínas de Neurofilamentos/inmunología , Receptores de Antígenos/inmunología , Animales , Autoantígenos/genética , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/patología , Linfocitos T CD4-Positivos/patología , Reacciones Cruzadas/genética , Reacciones Cruzadas/inmunología , Ratones , Ratones Noqueados , Vaina de Mielina/genética , Glicoproteína Mielina-Oligodendrócito/genética , Proteínas de Neurofilamentos/genética , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Receptores de Antígenos/genéticaRESUMEN
Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. However, identification and functional characterization of causal variants remain challenging. Here, we focused on the immunomodulatory role of a protective variant of histone deacetylase 7 (HDAC7). This variant (rs148755202, HDAC7.p.R166H) was identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analyses, we demonstrate that wild-type HDAC7 regulates genes essential for the function of Foxp3+ regulatory T cells (Tregs), an immunosuppressive subset of CD4 T cells that is generally dysfunctional in patients with MS. Moreover, Treg-specific conditional hemizygous deletion of HDAC7 increased the severity of experimental autoimmune encephalitis (EAE), a mouse model of neuroinflammation. In contrast, Tregs transduced with the protective HDAC7 R166H variant exhibited higher suppressive capacity in an in vitro functional assay, mirroring phenotypes previously observed in patient samples. In vivo modeling of the human HDAC7 R166H variant by generation of a knock-in mouse model bearing an orthologous R150H substitution demonstrated decreased EAE severity linked to transcriptomic alterations of brain-infiltrating Tregs, as assessed by single-cell RNA sequencing. Our data suggest that dysregulation of epigenetic modifiers, a distinct molecular class associated with disease risk, may influence disease onset. Last, our approach provides a template for the translation of genetic susceptibility loci to detailed functional characterization, using in vitro and in vivo modeling.
Asunto(s)
Esclerosis Múltiple , Linfocitos T Reguladores , Ratones , Animales , Humanos , Esclerosis Múltiple/genética , Estudio de Asociación del Genoma Completo , Linfocitos T CD4-Positivos , Histona Desacetilasas , Modelos Animales de EnfermedadRESUMEN
A key aspect of nearly all single-cell sequencing experiments is dissociation of intact tissues into single-cell suspensions. While many protocols have been optimized for optimal cell yield, they have often overlooked the effects that dissociation can have on ex vivo gene expression. Here, we demonstrate that use of enzymatic dissociation on brain tissue induces an aberrant ex vivo gene expression signature, most prominently in microglia, which is prevalent in published literature and can substantially confound downstream analyses. To address this issue, we present a rigorously validated protocol that preserves both in vivo transcriptional profiles and cell-type diversity and yield across tissue types and species. We also identify a similar signature in postmortem human brain single-nucleus RNA-sequencing datasets, and show that this signature is induced in freshly isolated human tissue by exposure to elevated temperatures ex vivo. Together, our results provide a methodological solution for preventing artifactual gene expression changes during fresh tissue digestion and a reference for future deeper analysis of the potential confounding states present in postmortem human samples.
Asunto(s)
Neuroglía , Transcriptoma , Encéfalo , Humanos , Microglía/metabolismo , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodosRESUMEN
Immune checkpoint blockade has demonstrated success in treating cancer but can lead to immune-related adverse events (irAEs), illustrating the centrality of these pathways in tolerance. Here, we describe programmed cell death protein 1 (PD-1) control of T cell responses, focusing on its unique restraint of regulatory T cell function. We examine successes and limitations of checkpoint blockade immunotherapy and review clinical and mechanistic features of irAEs. Last, we discuss strategies to modulate PD-1 blockade to enhance antitumor immunity while limiting autoimmunity.
Asunto(s)
Autoinmunidad , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Humanos , Neoplasias/terapia , Linfocitos T Reguladores/inmunologíaRESUMEN
Understanding the relationship between tumor and peripheral immune environments could allow longitudinal immune monitoring in cancer. Here, we examined whether T cells that share the same TCRαß and are found in both tumor and blood can be interrogated to gain insight into the ongoing tumor T cell response. Paired transcriptome and TCRαß repertoire of circulating and tumor-infiltrating T cells were analyzed at the single-cell level from matched tumor and blood from patients with metastatic melanoma. We found that in circulating T cells matching clonally expanded tumor-infiltrating T cells (circulating TILs), gene signatures of effector functions, but not terminal exhaustion, reflect those observed in the tumor. In contrast, features of exhaustion are displayed predominantly by tumor-exclusive T cells. Finally, genes associated with a high degree of blood-tumor TCR sharing were overexpressed in tumor tissue after immunotherapy. These data demonstrate that circulating TILs have unique transcriptional patterns that may have utility for the interrogation of T cell function in cancer immunotherapy.
Asunto(s)
Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/sangre , Melanoma/inmunología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/inmunología , Linfocitos T Citotóxicos/inmunología , Células Clonales , Citotoxicidad Inmunológica/genética , Humanos , Inmunoterapia , Melanoma/patología , Melanoma/terapia , Monitorización Inmunológica/métodos , Metástasis de la Neoplasia , Fenotipo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , TranscriptomaRESUMEN
Regulatory T (Treg) cells constitute a dynamic population that is essential for controlling immune responses in health and disease. Defects in Treg cell function and decreases in Treg cell numbers have been observed in patients with autoimmunity and the opposite effects on Treg cells occur in cancer settings. Current research on new therapies for these diseases is focused on modulating Treg cell function to increase or decrease suppressive activity in autoimmunity and cancer, respectively. In this regard, several co-inhibitory receptors that are preferentially expressed by Treg cells under homeostatic conditions have recently been shown to control Treg cell function and stability in different disease settings. These receptors could be amenable to therapeutic targeting aimed at modulating Treg cell function and plasticity. This Review summarizes recent data regarding the role of co-inhibitory molecules in the control of Treg cell function and stability, with a focus on their roles and potential therapeutic use in autoimmunity and cancer.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Receptores Coestimuladores e Inhibidores de Linfocitos T/efectos de los fármacos , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad , Sistemas de Liberación de Medicamentos , Humanos , Neoplasias/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
OBJECTIVE: To identify coinhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor-infiltrating T cells (TILs) from patients with glioblastoma multiforme may reveal novel targets for immunotherapy. METHODS: We collected fresh surgical resections and matched blood from patients with glioblastoma, blood and unmatched postmortem CNS tissue from patients with MS, and blood from healthy donors. The expression of TIGIT, CD226, and their shared ligand CD155 as well as PD-1 and PDL1 was assessed by both immunohistochemistry and flow cytometry. RESULTS: We found that TIGIT was highly expressed on glioblastoma-infiltrating T cells, but was near-absent from MS lesions. Conversely, lymphocytic expression of PD-1/PD-L1 was comparable between the 2 diseases. Moreover, TIGIT was significantly upregulated in circulating lymphocytes of patients with glioblastoma compared with healthy controls, suggesting recirculation of TILs. Expression of CD226 was also increased in glioblastoma, but this costimulatory receptor was expressed alongside TIGIT in the majority of tumor-infiltrating T cells, suggesting functional counteraction. CONCLUSIONS: The opposite patterns of TIGIT expression in the CNS between MS and glioblastoma reflects the divergent features of the immune response in these 2 CNS diseases. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.
Asunto(s)
Neoplasias del Sistema Nervioso Central/inmunología , Neoplasias del Sistema Nervioso Central/metabolismo , Glioblastoma/metabolismo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Receptores Inmunológicos/metabolismo , Adulto , Anciano , Neoplasias del Sistema Nervioso Central/sangre , Neoplasias del Sistema Nervioso Central/patología , Femenino , Glioblastoma/sangre , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/patología , Receptores Inmunológicos/sangre , Regulación hacia ArribaRESUMEN
Th1 Tregs are characterized by the acquisition of proinflammatory cytokine secretion and reduced suppressor activity. Th1 Tregs are found at increased frequency in autoimmune diseases, including type 1 diabetes and multiple sclerosis (MS). We have previously reported that in vitro stimulation with IL-12 recapitulates the functional and molecular features of MS-associated Th1 Tregs, revealing a central role for hyperactivation of the Akt pathway in their induction. TIGIT is a newly identified coinhibitory receptor that marks Tregs that specifically control Th1 and Th17 responses. Here, we report that signaling through TIGIT counteracts the action of IL-12 in inducing the Th1 program. Specifically, TIGIT signaling represses production of IFN-γ and T-bet expression and restores suppressor function in Tregs treated with IL-12. FoxO1 functional inhibition abolishes the protective effect of TIGIT, indicating that TIGIT signaling promotes FoxO1 nuclear localization. Consistent with this observation, signaling through TIGIT leads to a rapid suppression of Akt function and FoxO1 phosphorylation. Finally, TIGIT stimulation reduces the production of IFN-γ and corrects the suppressor defect of Tregs from patients with MS. Our results indicate an important role for TIGIT in controlling the functional stability of Tregs through repression of Akt, suggesting that the TIGIT pathway could be targeted for immunomodulatory therapies in human autoimmune disorders.
RESUMEN
Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non-small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor. They show that the oncometabolite 2-hydroxyglutarate (2HG), generated by mutated forms of isocitrate dehydrogenase (IDH1 and IDH2), reduces the expression of STAT1, thereby limiting the production of the chemokines CXCL9 and CXCL10. As a result, IDH1-mutated tumors are less effectively infiltrated by CD8+ T cells, contributing to tumor escape. Finally, in mice harboring syngeneic gliomas, an inhibitor of 2HG synthesis complemented vaccination to ameliorate tumor control. Understanding how to increase immune infiltration of gliomas represents a key first step in achieving tumor destruction through immunotherapy.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Glioma/inmunología , Glutaratos/inmunología , Escape del Tumor , Animales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Quimiocina CXCL9/genética , Quimiocina CXCL9/inmunología , Quimiocina CXCL9/metabolismo , Glioma/genética , Glioma/metabolismo , Glioma/patología , Glutaratos/metabolismo , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/inmunología , Isocitrato Deshidrogenasa/metabolismo , Mutación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Proteínas de Neoplasias/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismoRESUMEN
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.