RESUMEN
Aging is one of the biggest risk factors for cancer development. Over 85% of all cancers occur in individuals aged over 55 years, often accompanied by age-associated immune defects. Previous studies on the tumor microenvironment (TME) during aging have identified several factors, such as the roles of fibroblasts, immunosuppression, and metastasis. However, the aging-associated defects in anti-tumor immunity, particularly regarding T cells, remain underexplored. Recent findings by Zhivaki and colleagues suggest that age-related immune defects affecting anti-tumor responses involve reduced levels of CD8+ T cells and compromised dendritic cell (DC) functions such as antigen presentation and migration. Their study demonstrates that a hyperactive DC vaccine can restore DC functions in older mice. Furthermore, these hyperactive DCs, characterized by increased IL-1ß production and better migratory capability to the lymph node, promote the development of cytolytic CD4+ T cells exhibiting Th1-like phenotypes. This research reveals mechanisms underlying the response to hyperactive DC vaccines in older mice and highlights the critical role of cytolytic CD4+ T cells as substitutes for CD8+ T cells in driving anti-tumor immunity and achieving long-term tumor control in older mice.
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The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.
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Envejecimiento , Linfocitos T CD8-positivos , Células Dendríticas , Microambiente Tumoral , Animales , Microambiente Tumoral/inmunología , Linfocitos T CD8-positivos/inmunología , Ratones , Células Dendríticas/inmunología , Envejecimiento/inmunología , Ratones Endogámicos C57BL , Células Asesinas Naturales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Humanos , Neoplasias/inmunología , Línea Celular Tumoral , Femenino , Activación de Linfocitos/inmunologíaRESUMEN
A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma1,2. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance3. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.
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Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies after vaccination or infection. Although the signals responsible for initiating Tfh differentiation from naïve T cells have been studied, the signals controlling sequential developmental stages culminating in optimal effector function are not well understood. Here we use fate mapping strategies for the cytokine IL-21 to uncover sequential developmental stages of Tfh differentiation including a progenitor-like stage, a fully developed effector stage and a post-effector Tfh stage that maintains transcriptional and epigenetic features without IL-21 production. We find that progression through these stages are controlled intrinsically by the transcription factor FoxP1 and extrinsically by follicular regulatory T cells. Through selective deletion of Tfh stages, we show that these cells control antibody dynamics during distinct stages of the germinal center reaction in response to a SARS-CoV-2 vaccine. Together, these studies demonstrate the sequential phases of Tfh development and how they promote humoral immunity.
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Células T Auxiliares Foliculares , Linfocitos T Colaboradores-Inductores , Humanos , Vacunas contra la COVID-19 , Inmunidad Humoral , Centro Germinal , Diferenciación Celular , Factores de TranscripciónRESUMEN
Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.
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Inmunoterapia , Neoplasias , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia/métodos , Interferones/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 2/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.
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Recent success in the use of immunotherapy for a broad range of cancers has propelled the field of cancer immunology to the forefront of cancer research. As more and more young investigators join the community of cancer immunologists, the Arthur L. Irving Family Foundation Cancer Immunology Symposium provided a platform to bring this expanding and vibrant community together and support the development of the future leaders in the field. This commentary outlines the lessons that emerged from the inaugural symposium highlighting the areas of scientific and career development that are essential for professional growth in the field of cancer immunology and beyond. Leading scientists and clinicians in the field provided their experience on the topics of scientific trajectory, career trajectory, publishing, fundraising, leadership, mentoring, and collaboration. Herein, we provide a conceptual and practical framework for career development to the broader scientific community.
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Alergia e Inmunología/educación , Investigación Biomédica/métodos , Neoplasias/epidemiología , Médicos/organización & administración , Humanos , LiderazgoRESUMEN
T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.
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Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Memoria Inmunológica/inmunología , Antivirales/uso terapéutico , Diferenciación Celular/inmunología , Epítopos/genética , Hepatitis C Crónica/tratamiento farmacológico , Humanos , FenotipoRESUMEN
T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.
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Antígenos Virales/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Memoria Inmunológica/inmunología , 2-Naftilamina/uso terapéutico , Anilidas/uso terapéutico , Antivirales/uso terapéutico , Cromatina/metabolismo , Ciclopropanos/uso terapéutico , Epigénesis Genética/genética , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Proteínas del Grupo de Alta Movilidad/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Lactamas Macrocíclicas/uso terapéutico , Prolina/análogos & derivados , Prolina/uso terapéutico , Ribavirina/uso terapéutico , Ritonavir/uso terapéutico , Sulfonamidas/uso terapéutico , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Valina/uso terapéuticoRESUMEN
T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial - but not complete - normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes.
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Antirretrovirales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epigénesis Genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Adulto , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Estudios de Casos y Controles , Estudios de Seguimiento , Infecciones por VIH/virología , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Humanos , Activación de Linfocitos , Masculino , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Prospectivos , Receptores Inmunológicos/metabolismo , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
CD8+ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8+ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8+ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8+ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8+ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8+ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.
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Enfermedades Autoinmunes/inmunología , Autoinmunidad , Linfocitos T CD8-positivos/inmunología , Enfermedades Transmisibles/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Enfermedad Crónica , Enfermedades Transmisibles/genética , Enfermedades Transmisibles/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Epigénesis Genética , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fenotipo , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de SeñalRESUMEN
Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+ T cells and fewer Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3-/- mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.
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Neoplasias de la Mama , Inmunoterapia , Neoplasias Mamarias Experimentales , Microambiente Tumoral/inmunología , Animales , Biomarcadores de Tumor/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Linfocitos T CD8-positivos/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/terapia , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Transcriptoma/inmunologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Epithelial resident memory T (eTRM) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eTRM cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor ß (TGF-ß) epigenetically conditions resting naïve CD8+ T cells and prepares them for the formation of eTRM cells in a mouse model of skin vaccination. Naïve T cell conditioning occurs in lymph nodes (LNs), but not in the spleen, through major histocompatibility complex class I-dependent interactions with peripheral tissue-derived migratory dendritic cells (DCs) and depends on DC expression of TGF-ß-activating αV integrins. Thus, the preimmune T cell repertoire is actively conditioned for a specialized memory differentiation fate through signals restricted to LNs.
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Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Memoria Inmunológica , Factor de Crecimiento Transformador beta/metabolismo , Animales , Movimiento Celular , Epidermis/inmunología , Integrina alfaV/genética , Integrina alfaV/metabolismo , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Piel/inmunologíaRESUMEN
Lymph node fibroblastic reticular cells (FRCs) respond to signals from activated T cells by releasing nitric oxide, which inhibits T cell proliferation and restricts the size of the expanding T cell pool. Whether interactions with FRCs also support the function or differentiation of activated CD8+ T cells is not known. Here we report that encounters with FRCs enhanced cytokine production and remodeled chromatin accessibility in newly activated CD8+ T cells via interleukin-6. These epigenetic changes facilitated metabolic reprogramming and amplified the activity of pro-survival pathways through differential transcription factor activity. Accordingly, FRC conditioning significantly enhanced the persistence of virus-specific CD8+ T cells in vivo and augmented their differentiation into tissue-resident memory T cells. Our study demonstrates that FRCs play a role beyond restricting T cell expansion-they can also shape the fate and function of CD8+ T cells.
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Linfocitos T CD8-positivos/inmunología , Fibroblastos/fisiología , Ganglios Linfáticos/inmunología , Animales , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Reprogramación Celular , Ensamble y Desensamble de Cromatina , Citotoxicidad Inmunológica , Epigénesis Genética , Regulación de la Expresión Génica , Memoria Inmunológica , Interleucina-6/genética , Interleucina-6/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismoRESUMEN
CD8+ T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6+ progenitor exhausted and Tim-3+ terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8+ T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3+ cells without altering Slamf6+ numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8+ T cells enhanced Tim-3+ anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3+CD8+ T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.
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Adenocarcinoma/inmunología , Linfocitos T CD8-positivos/fisiología , Neoplasias del Colon/inmunología , Inmunoterapia/métodos , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Células Progenitoras Linfoides/fisiología , Melanoma/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Neoplasias Cutáneas/inmunología , Animales , Senescencia Celular , Citotoxicidad Inmunológica , Femenino , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Tolerancia Inmunológica , Interferón Tipo I/metabolismo , Masculino , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Transducción de Señal , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismoRESUMEN
T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+ TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8+ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+ T cells might be an important component of improving the response to checkpoint blockade.
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Anticuerpos Bloqueadores/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Melanoma Experimental/prevención & control , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Anticuerpos Bloqueadores/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Línea Celular Tumoral , Femenino , Humanos , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/virología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/virología , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/prevención & control , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/efectos de los fármacos , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Melanoma Experimental/inmunología , Melanoma Experimental/virología , Ratones Congénicos , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.
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Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteínas de Unión al ARN/metabolismo , Adenosina Desaminasa/genética , Animales , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Femenino , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunoterapia , Inflamación/genética , Inflamación/inmunología , Helicasa Inducida por Interferón IFIH1/metabolismo , Interferones/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/radioterapia , Ratones , Ratones Endogámicos C57BL , Fenotipo , Edición de ARN , ARN Bicatenario/genética , Proteínas de Unión al ARN/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
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Antígeno B7-H1/genética , Linfocitos T CD8-positivos/inmunología , Reprogramación Celular/genética , Epigénesis Genética , Memoria Inmunológica/genética , Animales , Antígeno B7-H1/antagonistas & inhibidores , Linfocitos T CD8-positivos/trasplante , Linaje de la Célula/genética , Reprogramación Celular/inmunología , Femenino , Redes Reguladoras de Genes , Inmunoterapia , Interleucina-7/metabolismo , Ratones , Ratones Endogámicos C57BL , Transcripción GenéticaRESUMEN
Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.