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1.
Cell ; 187(11): 2690-2702.e17, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38723627

RESUMEN

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.


Asunto(s)
Linfocitos T CD8-positivos , Inmunoterapia , Linfocitos Infiltrantes de Tumor , Ratones Endogámicos C57BL , Microambiente Tumoral , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Relojes Circadianos , Ritmo Circadiano , Células Endoteliales/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Melanoma/terapia , Melanoma/patología , Microambiente Tumoral/inmunología
2.
Cell ; 186(9): 1846-1862.e26, 2023 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-37028428

RESUMEN

The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.


Asunto(s)
Limosilactobacillus reuteri , Melanoma , Microambiente Tumoral , Humanos , Dieta , Inhibidores de Puntos de Control Inmunológico , Limosilactobacillus reuteri/metabolismo , Melanoma/terapia , Triptófano/metabolismo , Linfocitos T CD8-positivos/inmunología , Receptores de Hidrocarburo de Aril/agonistas
3.
Nat Immunol ; 25(2): 268-281, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38195702

RESUMEN

Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.


Asunto(s)
Melanoma , Receptor de Factor de Crecimiento Nervioso , Humanos , Receptor de Factor de Crecimiento Nervioso/genética , Receptor de Factor de Crecimiento Nervioso/metabolismo , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Tropomiosina , Melanoma/terapia , Receptor trkA/genética , Receptor trkA/metabolismo , Citoprotección , Inhibidores de Puntos de Control Inmunológico , Células T de Memoria , Terapia de Inmunosupresión , Inmunoterapia , Receptores de Antígenos de Linfocitos T
4.
Cell ; 179(1): 236-250.e18, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31495571

RESUMEN

Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocyte (TIL)-based or anti- programmed death 1 (PD1) immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins in total and ∼4,500 proteins across most samples in each dataset. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders than in non-responders in both treatments. To elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or CRISPR-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby increasing sensitivity to T cell mediated killing both in vitro and in vivo. Altogether, our proteomic analyses revealed association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.


Asunto(s)
Inmunoterapia/métodos , Melanoma/metabolismo , Melanoma/terapia , Mitocondrias/metabolismo , Proteómica/métodos , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/terapia , Traslado Adoptivo/métodos , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Estudios de Cohortes , Femenino , Humanos , Metabolismo de los Lípidos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/inmunología , Resultado del Tratamiento , Adulto Joven
5.
Nat Immunol ; 22(5): 595-606, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33903766

RESUMEN

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Hemo-Oxigenasa 1/metabolismo , Neoplasias Pulmonares/inmunología , Melanoma/inmunología , Neoplasias Cutáneas/inmunología , Macrófagos Asociados a Tumores/inmunología , Animales , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/sangre , Línea Celular Tumoral/trasplante , Quimioterapia Adyuvante/métodos , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/inmunología , Femenino , Hemo/metabolismo , Hemo-Oxigenasa 1/antagonistas & inhibidores , Hemo-Oxigenasa 1/sangre , Hemo-Oxigenasa 1/genética , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Melanoma/mortalidad , Melanoma/secundario , Melanoma/terapia , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Células Progenitoras Mieloides/inmunología , Células Progenitoras Mieloides/metabolismo , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/metabolismo
6.
Immunity ; 57(10): 2466-2482.e12, 2024 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-39276771

RESUMEN

Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.


Asunto(s)
Linfocitos T CD8-positivos , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor , Melanoma , Receptores de Antígenos de Linfocitos T , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Melanoma/terapia , Inmunoterapia Adoptiva/métodos , Linfocitos T CD8-positivos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Células Clonales , Animales , Resultado del Tratamiento
7.
Cell ; 175(4): 984-997.e24, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30388455

RESUMEN

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.


Asunto(s)
Antineoplásicos/uso terapéutico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Melanoma/inmunología , Inhibidores de Proteínas Quinasas/uso terapéutico , Linfocitos T/inmunología , Escape del Tumor , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Femenino , Humanos , Inmunoterapia/métodos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/terapia , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología
8.
Cell ; 175(4): 998-1013.e20, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30388456

RESUMEN

Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunoterapia/métodos , Melanoma/inmunología , Transcriptoma , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos CD/inmunología , Antineoplásicos Inmunológicos/inmunología , Antineoplásicos Inmunológicos/farmacología , Apirasa/antagonistas & inhibidores , Apirasa/inmunología , Línea Celular Tumoral , Humanos , Antígenos Comunes de Leucocito/antagonistas & inhibidores , Antígenos Comunes de Leucocito/inmunología , Melanoma/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Factor 1 de Transcripción de Linfocitos T/metabolismo
9.
Cell ; 170(6): 1109-1119.e10, 2017 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-28886381

RESUMEN

Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, as well as IFN-γ gene expression on several cell subsets in tumors after talimogene laherparepvec treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-γ signature. These findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment. VIDEO ABSTRACT.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Melanoma/terapia , Viroterapia Oncolítica/efectos adversos , Terapia Combinada , Herpesviridae/genética , Humanos , Inmunoterapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente Tumoral
10.
Cell ; 171(4): 934-949.e16, 2017 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-29033130

RESUMEN

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Inmunoterapia , Melanoma/terapia , Microambiente Tumoral , Estudio de Asociación del Genoma Completo , Humanos , Melanoma/genética , Melanoma/inmunología , Nivolumab , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T , Transcriptoma
11.
Cell ; 170(6): 1120-1133.e17, 2017 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-28803728

RESUMEN

Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms.


Asunto(s)
Antígeno CTLA-4/antagonistas & inhibidores , Melanoma/inmunología , Melanoma/terapia , Metástasis de la Neoplasia/inmunología , Metástasis de la Neoplasia/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Subgrupos de Linfocitos T/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Regulación de la Expresión Génica , Humanos , Inmunoterapia , Melanoma/patología , Ratones , Ratones Endogámicos C57BL , Metástasis de la Neoplasia/patología , Análisis de la Célula Individual , Transcripción Genética
12.
Cell ; 168(3): 487-502.e15, 2017 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-28111070

RESUMEN

Immune responses involve coordination across cell types and tissues. However, studies in cancer immunotherapy have focused heavily on local immune responses in the tumor microenvironment. To investigate immune activity more broadly, we performed an organism-wide study in genetically engineered cancer models using mass cytometry. We analyzed immune responses in several tissues after immunotherapy by developing intuitive models for visualizing single-cell data with statistical inference. Immune activation was evident in the tumor and systemically shortly after effective therapy was administered. However, during tumor rejection, only peripheral immune cells sustained their proliferation. This systemic response was coordinated across tissues and required for tumor eradication in several immunotherapy models. An emergent population of peripheral CD4 T cells conferred protection against new tumors and was significantly expanded in patients responding to immunotherapy. These studies demonstrate the critical impact of systemic immune responses that drive tumor rejection.


Asunto(s)
Inmunoterapia , Neoplasias/inmunología , Neoplasias/terapia , Subgrupos de Linfocitos T/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Médula Ósea/inmunología , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Tolerancia Inmunológica , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Tejido Linfoide/inmunología , Masculino , Melanoma/inmunología , Melanoma/terapia , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/terapia , Microambiente Tumoral
13.
Cell ; 167(6): 1540-1554.e12, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-27912061

RESUMEN

Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.


Asunto(s)
Antígeno CTLA-4/antagonistas & inhibidores , Melanoma/inmunología , Melanoma/terapia , Radioinmunoterapia , Animales , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Xenoinjertos , Humanos , Interferones/inmunología , Melanoma/tratamiento farmacológico , Melanoma/radioterapia , Ratones , Trasplante de Neoplasias , Factor de Transcripción STAT1 , Linfocitos T/inmunología
14.
Cell ; 162(6): 1206-8, 2015 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-26359979

RESUMEN

It is thought that cancer cells engage in Warburg metabolism to meet intrinsic biosynthetic requirements of cell growth and proliferation. Papers by Chang et al. and Ho et al. show that Warburg metabolism enables tumor cells to restrict glucose availability to T cells, suppressing anti-tumor immunity.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Glucólisis , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Melanoma/inmunología , Melanoma/terapia , Monitorización Inmunológica , Neoplasias/metabolismo , Fosfoenolpiruvato/metabolismo , Microambiente Tumoral , Animales
15.
Cell ; 162(5): 938-9, 2015 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-26317460

RESUMEN

DNA demethylating agents are approved for some blood malignancies and are under active investigation in solid tumors, but how these drugs work has remained unclear. In this issue of Cell, two groups show that these agents activate a toxic cellular antiviral program through transcriptional activation of endogenous retroviral sequences.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Azacitidina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Metilación de ADN/efectos de los fármacos , Interferón Tipo I/inmunología , Melanoma/inmunología , Melanoma/terapia , Animales , Femenino , Humanos
16.
Cell ; 162(6): 1217-28, 2015 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-26321681

RESUMEN

Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca(2+)-NFAT signaling and effector functions by repressing sarco/ER Ca(2+)-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Melanoma/terapia , Monitorización Inmunológica , Fosfoenolpiruvato/metabolismo , Microambiente Tumoral , Animales , Calcio/metabolismo , Retículo Endoplásmico/metabolismo , Glucólisis , Hexoquinasa/metabolismo , Inmunoterapia , Ratones , Factores de Transcripción NFATC/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/inmunología
17.
Cell ; 162(5): 974-86, 2015 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-26317466

RESUMEN

We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.


Asunto(s)
Metilación de ADN/efectos de los fármacos , Interferón Tipo I/inmunología , Melanoma/inmunología , Melanoma/terapia , Animales , Azacitidina/farmacología , Línea Celular Tumoral , Metilasas de Modificación del ADN/antagonistas & inhibidores , Retrovirus Endógenos/genética , Femenino , Humanos , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Ratones , Ratones Endogámicos C57BL , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , ARN Bicatenario/metabolismo
18.
Immunity ; 53(3): 564-580.e9, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32750334

RESUMEN

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/inmunología
19.
Nature ; 614(7946): 136-143, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36470303

RESUMEN

The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime1,2. However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance.


Asunto(s)
Linfocitos T CD8-positivos , Ritmo Circadiano , Células Dendríticas , Melanoma , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Inmunoterapia/métodos , Melanoma/inmunología , Melanoma/patología , Melanoma/terapia , Ratones Endogámicos C57BL , Antígeno B7-1 , Antígenos de Neoplasias/inmunología , Ganglios Linfáticos , Ritmo Circadiano/inmunología
20.
Nature ; 622(7982): 383-392, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37731001

RESUMEN

CD8+ T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion1. Although it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the ß1-adrenergic receptor ADRB1. We identify that exhausted CD8+ T cells increase ADRB1 expression and that exposure of ADRB1+ T cells to catecholamines suppresses their cytokine production and proliferation. Exhausted CD8+ T cells cluster around sympathetic nerves in an ADRB1-dependent manner. Ablation of ß1-adrenergic signalling limits the progression of T cells towards the exhausted state in chronic infection and improves effector functions when combined with immune checkpoint blockade (ICB) in melanoma. In a pancreatic cancer model resistant to ICB, ß-blockers and ICB synergize to boost CD8+ T cell responses and induce the development of tissue-resident memory-like T cells. Malignant disease is associated with increased catecholamine levels in patients2,3, and our results establish a connection between the sympathetic stress response, tissue innervation and T cell exhaustion. Here, we uncover a new mechanism by which blocking ß-adrenergic signalling in CD8+ T cells rejuvenates anti-tumour functions.


Asunto(s)
Linfocitos T CD8-positivos , Catecolaminas , Receptores Adrenérgicos beta 1 , Sistema Nervioso Simpático , Agotamiento de Células T , Humanos , Antígenos/inmunología , Antígenos/metabolismo , Catecolaminas/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/terapia , Células T de Memoria/citología , Células T de Memoria/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Receptores Adrenérgicos beta 1/metabolismo , Sistema Nervioso Simpático/inmunología , Sistema Nervioso Simpático/fisiología , Estrés Fisiológico
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