RESUMEN
Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
Asunto(s)
COVID-19/complicaciones , Cardiotónicos/uso terapéutico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Cardiopatías/tratamiento farmacológico , Quinazolinonas/uso terapéutico , Factores de Transcripción/antagonistas & inhibidores , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Citocinas/metabolismo , Femenino , Cardiopatías/etiología , Células Madre Embrionarias Humanas , Humanos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción/metabolismo , Tratamiento Farmacológico de COVID-19RESUMEN
The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.
Asunto(s)
Neoplasias/inmunología , Inmunidad Adaptativa , Animales , Humanos , Inmunidad Innata , Vigilancia Inmunológica , Neoplasias/fisiopatología , Neoplasias/terapiaRESUMEN
Natural killer (NK) cells belong to the innate immune system and contribute to protecting the host through killing of infected, foreign, stressed or transformed cells. Additionally, via cellular cross-talk, NK cells orchestrate antitumor immune responses. Hence, significant efforts have been undertaken to exploit the therapeutic properties of NK cells in cancer. Current strategies in preclinical and clinical development include adoptive transfer therapies, direct stimulation, recruitment of NK cells into the tumor microenvironment (TME), blockade of inhibitory receptors that limit NK cell functions, and therapeutic modulation of the TME to enhance antitumor NK cell function. In this Review, we introduce the NK cell-cancer cycle to highlight recent advances in NK cell biology and to discuss the progress and problems of NK cell-based cancer immunotherapies.
Asunto(s)
Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Animales , Humanos , Microambiente Tumoral/inmunologíaRESUMEN
Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inflamación/inmunología , Células Asesinas Naturales/inmunología , Leishmania donovani/fisiología , Leishmaniasis Visceral/inmunología , Malaria/inmunología , Proteínas de la Membrana/metabolismo , Plasmodium/fisiología , Animales , Células Cultivadas , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Exocitosis , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Vesículas Secretoras/metabolismoRESUMEN
Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-ß-signaling-dependent conversion of NK cells (CD49a-CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b-Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-ß-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.
Asunto(s)
Reprogramación Celular/inmunología , Fibrosarcoma/inmunología , Neoplasias Gastrointestinales/inmunología , Tumores del Estroma Gastrointestinal/inmunología , Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Neoplasias Experimentales/inmunología , Escape del Tumor/inmunología , Animales , Estudios de Casos y Controles , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Células Asesinas Naturales/citología , Linfocitos/citología , Linfocitos/inmunología , Ratones , Análisis de Secuencia de ARN , Transducción de Señal , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
The regulatory mechanisms controlling natural killer (NK) cells in the tumor microenvironment remain unknown. In this issue, Ni. et al. provide evidence that the transcription factor HIF-1α acts as a key negative regulator of NK cell metabolic fitness in the tumor microenvironment that critically impedes NK cell anti-tumor immune responses.
Asunto(s)
Neoplasias , Factores de Transcripción , Humanos , Células Asesinas Naturales , Análisis de Secuencia de ARN , Microambiente TumoralRESUMEN
Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8+ T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8+ T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4R24C (Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8+ T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4R24C, promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4R24C antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies.
Asunto(s)
Traslado Adoptivo/métodos , Linfocitos T CD8-positivos/trasplante , Epítopos de Linfocito T/inmunología , Melanoma/inmunología , Melanoma/terapia , Escape del Tumor/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Epítopos de Linfocito T/genética , Técnicas de Inactivación de Genes , Inhibidores de Puntos de Control Inmunológico/farmacología , Ratones , Ratones Endogámicos C57BL , Células Mieloides/citología , Células Mieloides/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Humanos , Inhibidores de Puntos de Control Inmunológico/inmunología , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Transcriptoma/inmunología , Microambiente Tumoral/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/inmunología , Linfocitos T CD8-positivos/inmunología , Receptores Virales/inmunología , Animales , Línea Celular , Línea Celular Tumoral , Células HEK293 , Humanos , Inhibidores de Puntos de Control Inmunológico/inmunología , Inmunoterapia/métodos , Células Jurkat , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Melanoma/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Alteration in the expression of cell-surface proteins is a common consequence of malignant transformation. Natural killer (NK) cells use an array of germline-encoded activating and inhibitory receptors that scan for altered protein-expression patterns, but tumor evasion of detection by the immune system is now recognized as one of the hallmarks of cancer. NK cells display rapid and potent immunity to metastasis or hematological cancers, and major efforts are now being undertaken to fully exploit NK cell anti-tumor properties in the clinic. Diverse approaches encompass the development of large-scale NK cell-expansion protocols for adoptive transfer, the establishment of a microenvironment favorable to NK cell activity, the redirection of NK cell activity against tumor cells and the release of inhibitory signals that limit NK cell function. In this Review we detail recent advances in NK cell-based immunotherapies and discuss the advantages and limitations of these strategies.
Asunto(s)
Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Neoplasias/terapia , Adyuvantes Inmunológicos/uso terapéutico , Animales , Antígenos de Neoplasias/inmunología , Citocinas/metabolismo , Citotoxicidad Inmunológica , Predicción , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunidad Innata , Inmunofenotipificación , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Interleucina-15/fisiología , Células Asesinas Naturales/trasplante , Ratones , Neoplasias/inmunología , Neoplasias/patología , Receptores de Células Asesinas Naturales/inmunología , Proteínas Recombinantes de Fusión/inmunología , Proteínas de Dominio T Box/fisiología , Escape del Tumor , Microambiente Tumoral/inmunologíaRESUMEN
The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.
Asunto(s)
Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Neoplasias/terapia , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Animales , Proliferación Celular/genética , Citotoxicidad Inmunológica/genética , Vigilancia Inmunológica , Interferón gamma/metabolismo , Interleucina-15/metabolismo , Janus Quinasa 1/metabolismo , Activación de Linfocitos/genética , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Terapia Molecular Dirigida , Neoplasias/inmunología , Transducción de Señal/genética , Proteínas Supresoras de la Señalización de Citocinas/genéticaRESUMEN
CD96, CD226 (DNAM-1) and TIGIT belong to an emerging family of receptors that interact with nectin and nectin-like proteins. CD226 activates natural killer (NK) cell-mediated cytotoxicity, whereas TIGIT reportedly counterbalances CD226. In contrast, the role of CD96, which shares the ligand CD155 with CD226 and TIGIT, has remained unclear. In this study we found that CD96 competed with CD226 for CD155 binding and limited NK cell function by direct inhibition. As a result, Cd96(-/-) mice displayed hyperinflammatory responses to the bacterial product lipopolysaccharide (LPS) and resistance to carcinogenesis and experimental lung metastases. Our data provide the first description, to our knowledge, of the ability of CD96 to negatively control cytokine responses by NK cells. Blocking CD96 may have applications in pathologies in which NK cells are important.
Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Células Asesinas Naturales/inmunología , Receptores Inmunológicos/metabolismo , Animales , Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Citotoxicidad Inmunológica/genética , Lipopolisacáridos/inmunología , Neoplasias Pulmonares/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nectinas , Metástasis de la Neoplasia , Neoplasias Experimentales/inmunología , Neumonía/inmunología , Unión Proteica/genética , Receptores Virales/metabolismoRESUMEN
Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors.
Asunto(s)
Inmunoterapia/métodos , Neoplasias Experimentales/terapia , Neutrófilos/inmunología , Proteínas Proto-Oncogénicas c-met/inmunología , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/inmunología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Estimación de Kaplan-Meier , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Neutrófilos/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
While intracellular adenosine triphosphate (ATP) occupies a key position in the bioenergetic metabolism of all the cellular compartments that form the tumor microenvironment (TME), extracellular ATP operates as a potent signal transducer. The net effects of purinergic signaling on the biology of the TME depend not only on the specific receptors and cell types involved, but also on the activation status of cis- and trans-regulatory circuitries. As an additional layer of complexity, extracellular ATP is rapidly catabolized by ectonucleotidases, culminating in the accumulation of metabolites that mediate distinct biological effects. Here, we discuss the molecular and cellular mechanisms through which ATP and its degradation products influence cancer immunosurveillance, with a focus on therapeutically targetable circuitries.
Asunto(s)
Adenosina Trifosfato/inmunología , Adenosina Trifosfato/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Animales , Humanos , Transducción de Señal/inmunología , Microambiente Tumoral/inmunología , Microambiente Tumoral/fisiologíaRESUMEN
The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.
Asunto(s)
Diferenciación Celular/inmunología , Proteína 2 Inhibidora de la Diferenciación/inmunología , Interleucina-15/inmunología , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Animales , Linaje de la Célula/inmunología , Células Cultivadas , Femenino , Citometría de Flujo , Masculino , Ratones , Ratones Mutantes , Receptores de Interleucina-15/inmunología , Receptores de Interleucina-15/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismoRESUMEN
The development and function of natural killer (NK) cells is regulated by the interaction of inhibitory receptors of the Ly49 family with distinct peptide-laden major histocompatibility complex (MHC) class I molecules, although whether the Ly49 family is able bind to other MHC class I-like molecules is unclear. Here we found that the prototypic inhibitory receptor Ly49A bound the highly conserved nonclassical MHC class I molecule H2-M3 with an affinity similar to its affinity for H-2D(d). The specific recognition of H2-M3 by Ly49A regulated the 'licensing' of NK cells and mediated 'missing-self' recognition of H2-M3-deficient bone marrow. Host peptide-H2-M3 was required for optimal NK cell activity against experimental metastases and carcinogenesis. Thus, nonclassical MHC class I molecules can act as cognate ligands for Ly49 molecules. Our results provide insight into the various mechanisms that lead to NK cell tolerance.