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How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.
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Presentación de Antígeno/inmunología , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/inmunología , Oncogenes , ARN Largo no Codificante/genética , Escape del Tumor/genética , Escape del Tumor/inmunología , Adenoma/genética , Adenoma/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Ratones , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In order to fuel their relentless expansion, cancers must expand their vasculature to augment delivery of oxygen and essential nutrients. The disordered web of irregular vessels that results, however, leaves gaps in oxygen delivery that foster tumor hypoxia. At the same time, tumor cells increase their oxidative metabolism to cope with the energetic demands of proliferation, which further worsens hypoxia due to heightened oxygen consumption. In these hypoxic, nutrient-deprived environments, tumors and suppressive stroma evolve to flourish while antitumor immunity collapses due to a combination of energetic deprivation, toxic metabolites, acidification, and other suppressive signals. Reversal of cancer hypoxia thus has the potential to increase the survival and effector function of tumor-infiltrating T cells, as well as to resensitize tumors to immunotherapy. Early clinical trials combining hypoxia reduction with immune checkpoint blockade have shown promising results in treating patients with advanced, metastatic, and therapeutically refractory cancers.
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Neoplasias , Microambiente Tumoral , Humanos , Hipoxia/metabolismo , Hipoxia/patología , Hipoxia/terapia , Inmunoterapia/métodos , Linfocitos TRESUMEN
Advances in our understanding of tumor immune biology and development of cancer immunotherapies have led to improved outcomes for patients that suffer from aggressive cancers such as metastatic melanoma. Despite these advances, a significant proportion of patients still fail to benefit, and as a result, attention has shifted to understanding how cancer cells escape immune destruction. Of particular interest is the metabolic landscape of the tumor microenvironment, as recent studies have demonstrated how both competition for essential nutrients and depletion of specific amino acids can promote T cell dysfunction. Here, we will discuss the major energetic pathways engaged by both T cells and cancer cells, metabolic substrates present in the tumor microenvironment, and emerging therapeutic strategies that seek to improve T cell metabolic fitness and bolster the antitumor immune response.
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Resistencia a Antineoplásicos/inmunología , Inmunoterapia/efectos adversos , Melanoma/terapia , Neoplasias/terapia , Humanos , Melanoma/inmunología , Enfermedades Mitocondriales , Metástasis de la Neoplasia , Neoplasias/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
The driver and passenger mutations accumulated in the process of malignant transformation offer an adequate spectrum of immune visible alterations to the cellular proteome and resulting peptidome to render these cancers targetable-and, in theory, rejectable-by the host T cell immune response. In addition, cancers often overexpress tissue-specific and developmental antigens to which immune tolerance is incomplete. Sometimes, virally transferred oncogenes drive malignant transformation and remain expressed throughout the cancer. Despite this state of antigenic sufficiency, cancer grows progressively and overcomes all efforts of the host immune system to contain it. While therapeutic cancer vaccination can mobilize high frequencies of tumor-specific T cells, these responses remain subject to intratumoral attenuation. Antibody modulation of T cell function through checkpoint blockade or costimulatory activation can restore survival, proliferation, and effector function to these tumor-infiltrating T cells and convert otherwise subtherapeutic vaccines into potentially curative cancer immunotherapeutics.
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Antígeno CTLA-4/administración & dosificación , Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Animales , Antígeno CTLA-4/inmunología , Vacunas contra el Cáncer/inmunología , Transformación Celular Neoplásica/inmunología , Femenino , Predicción , Humanos , Factores Inmunológicos/administración & dosificación , Masculino , Neoplasias/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/terapia , Medición de Riesgo , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
Activation of the stimulator of interferon genes (STING) pathway by both exogenous and endogenous cytosolic DNA results in the production of interferon beta (IFN-ß) and is required for the generation of cytotoxic T-cell priming against tumor antigens. In the clinical setting, pharmacological stimulation of the STING pathway has the potential to synergize with immunotherapy antibodies by boosting anti-tumor immune responses. We report the discovery of two highly potent cyclic dinucleotide STING agonists, IACS-8803 and IACS-8779, which show robust activation of the STING pathway in vitro and a superior systemic anti-tumor response in the B16 murine model of melanoma when compared to one of the clinical benchmark compounds.
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Antineoplásicos/química , Compuestos Heterocíclicos/química , Interferón beta/metabolismo , Melanoma Experimental/inmunología , Melanoma/inmunología , Nucleótidos Cíclicos/antagonistas & inhibidores , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Línea Celular , Citosol/metabolismo , Compuestos Heterocíclicos/farmacología , Humanos , Inmunidad Innata , Inmunoterapia/métodos , Proteínas de la Membrana/inmunología , Ratones , Fosfatos/metabolismo , Transducción de Señal , Microambiente TumoralRESUMEN
Antibody modulation of T-cell coinhibitory (e.g., CTLA-4) or costimulatory (e.g., 4-1BB) receptors promotes clinical responses to a variety of cancers. Therapeutic cancer vaccination, in contrast, has produced limited clinical benefit and no curative therapies. The E6 and E7 oncoproteins of human papilloma virus (HPV) drive the majority of genital cancers, and many oropharyngeal tumors. We discovered 15-19 amino acid peptides from HPV-16 E6/E7 for which induction of T-cell immunity correlates with disease-free survival in patients treated for high-grade cervical neoplasia. We report here that intranasal vaccination with these peptides and the adjuvant alpha-galactosylceramide elicits systemic and mucosal T-cell responses leading to reduced HPV(+) TC-1 tumor growth and prolonged survival in mice. We hypothesized that the inability of these T cells to fully reject established tumors resulted from suppression in the tumor microenvironment which could be ameliorated through checkpoint modulation. Combining this E6/E7 peptide vaccine with checkpoint blockade produced only modest benefit; however, coadministration with a 4-1BB agonist antibody promoted durable regression of established genital TC-1 tumors. Relative to other therapies tested, this combination of vaccine and α4-1BB promoted the highest CD8(+) versus regulatory FoxP3(+) T-cell ratios, elicited 2- to 5-fold higher infiltration by E7-specific CTL, and evoked higher densities of highly cytotoxic TcEO (T cytotoxic Eomesodermin) CD8 (>70-fold) and ThEO (T helper Eomesodermin) CD4 (>17-fold) T cells. These findings have immediate clinical relevance both in terms of the direct clinical utility of the vaccine studied and in illustrating the potential of 4-1BB antibody to convert therapeutic E6/E7 vaccines already in clinical trials into curative therapies.
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Anticuerpos/química , Vacunas contra Papillomavirus/química , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/agonistas , Animales , Separación Celular , Citocinas/metabolismo , Femenino , Citometría de Flujo , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Proteínas Oncogénicas Virales/química , Papillomaviridae , Proteínas E7 de Papillomavirus/química , Vacunas contra Papillomavirus/inmunología , Péptidos/química , Bazo/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Vacunas de Subunidad/química , Vacunas de Subunidad/inmunología , Vagina/patologíaRESUMEN
The discovery that antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte-associated protein 4 (CTLA-4) can restore tumor immunity against many murine transplantable tumors leading to complete rejection of established cancer forever changed the field of immunotherapy. In more robust murine models as well as human cancer, however, CTLA-4 blockade alone can slow tumor growth and extend patient survival, but is rarely curative. Subsequent studies have revealed a large family of T cell immune checkpoint receptors which tumors engage to shield themselves from host immunity. As with CTLA-4, blockade of one of these additional inhibitory receptors, programmed death 1, has led to remarkable therapeutic responses against tumors of multiple lineages. Checkpoint monotherapy has demonstrated that durable, immune-mediated cures of established metastatic cancers are possible, yet the percentage of patients experiencing these outcomes remains low due to both redundant mechanisms of immune suppression in the tumor and limiting toxicity associated with some therapies. Thus, extending the curative potential of immunotherapy to a larger percentage of patients with a broader spectrum of malignancies will likely require combinations of co-inhibitory blockade and co-stimulatory activation designed to peel back multiple layers of tumor immune suppression while at the same time minimizing immune-mediated toxicity. As over a dozen T cell immune checkpoints and an additional dozen more co-stimulatory receptors have now been described, the challenge before us is to identify the most advantageous combinations of these agents based on the knowledge of their underlying biology and preclinical studies in murine tumor models.
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Antígenos de Neoplasias/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ligando 4-1BB/metabolismo , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos de Neoplasias/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Humanos , Inmunoterapia , Ipilimumab , Ratones , Neoplasias/genética , Neoplasias/terapia , Linfocitos T/inmunologíaRESUMEN
We previously showed that ablation of tumor hypoxia can sensitize tumors to immune checkpoint blockade (ICB). Here, we used a Kras+/G12D TP53+/R172H Pdx1-Cre-derived (KPC-derived) model of pancreatic adenocarcinoma to examine the tumor response and adaptive resistance mechanisms involved in response to 2 established methods of hypoxia-reducing therapy: the hypoxia-activated prodrug TH-302 and vascular endothelial growth factor receptor 2 (VEGFR-2) blockade. The combination of both modalities normalized tumor vasculature, increased DNA damage and cell death, and delayed tumor growth. In contrast with prior cancer models, the combination did not alleviate overall tissue hypoxia or sensitize these KPC tumors to ICB therapy despite qualitative improvements to the CD8+ T cell response. Bulk tumor RNA sequencing, flow cytometry, and adoptive myeloid cell transfer suggested that treated tumor cells increased their capacity to recruit granulocytic myeloid-derived suppressor cells (G-MDSCs) through CCL9 secretion. Blockade of the CCL9/CCR1 axis could limit G-MDSC migration, and depletion of Ly6G-positive cells could sensitize tumors to the combination of TH-302, anti-VEGFR-2, and ICB. Together, these data suggest that pancreatic tumors modulate G-MDSC migration as an adaptive response to vascular normalization and that these immunosuppressive myeloid cells act in a setting of persistent hypoxia to maintain adaptive immune resistance.
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Adenocarcinoma , Células Supresoras de Origen Mieloide , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Adenocarcinoma/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Hipoxia/metabolismoRESUMEN
Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors. SIGNIFICANCE: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING.
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Interferón Tipo I , Leucemia Mieloide Aguda , Humanos , Isoformas de Proteínas/genética , Leucemia Mieloide Aguda/genética , Empalme Alternativo/genética , Interferón Tipo I/genética , Línea Celular , Microambiente TumoralRESUMEN
Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-ERRα-hepatocyte growth factor axis that form bidirectional hepatocyte-neutrophil cross-talk to repair and regenerate the liver.
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Introduction: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge. Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab. Results: The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of anti-tumor macrophages and activated T-cells, potentially explaining its better response. Conclusions: Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.
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STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.
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Glioblastoma , Proteínas de la Membrana , Microambiente Tumoral , Animales , Glioblastoma/inmunología , Glioblastoma/patología , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Microambiente Tumoral/inmunología , Ratones , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/agonistas , Humanos , Línea Celular Tumoral , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genéticaRESUMEN
Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding alphaPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-gamma production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-gamma/TNF-alpha double-producing CD8(+) T cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.
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Antígenos de Diferenciación/inmunología , Células de la Médula Ósea/inmunología , Granzimas/inmunología , Melanoma Experimental/inmunología , Linfocitos T Reguladores/inmunología , Animales , Vacunas contra el Cáncer/inmunología , Interferón gamma/biosíntesis , Receptor de Muerte Celular Programada 1RESUMEN
Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism of immune escape in patients with acute myeloid leukemia after HSCT. Here we report that treatment with the tyrosine kinase inhibitor, dasatinib, and an anti-PD-1 antibody in preclinical models of Philadelphia chromosome positive B-cell acute lymphoblastic leukemia is highly active. The dasatinib and anti-PD-1 combination reduces tumor burden, is efficacious, and extends survival. Mechanistically, we found that treatment with dasatinib significantly increased MHC II expression on the surface of antigen-presenting cells (APC) in a tumor microenvironment-independent fashion and caused influx of APC cells into the leukemic bone marrow. Finally, the induction of MHC II may potentiate immune memory by impairing leukemic engraftment in mice previously cured with dasatinib, after re-inoculation of leukemia cells. In summary, our data suggests that anti-PD-1 therapy may enhance the killing ability of dasatinib via dasatinib driven APC growth and expansion and upregulation of MHC II expression, leading to antileukemic immune rewiring.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptor de Muerte Celular Programada 1 , Animales , Humanos , Ratones , Dasatinib/farmacología , Dasatinib/uso terapéutico , Antígenos de Histocompatibilidad Clase II , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Microambiente TumoralRESUMEN
BACKGROUND: The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms. METHODS: The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8. RESULTS: QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector-to-suppressor ratios when implanted subcutaneously (sensitive), which are absent on implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden. CONCLUSIONS: These syngeneic QPP models of glioblastoma demonstrate clinically relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies.
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Glioblastoma , Humanos , Animales , Ratones , Glioblastoma/patología , Ratones Endogámicos C57BL , Inmunoterapia/métodos , Linfocitos T/metabolismo , Microambiente TumoralRESUMEN
Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance.
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Lipólisis , ARN Nucleolar Pequeño , Animales , Ratones , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Interleucina-15/metabolismo , Rejuvenecimiento , Adipocitos/metabolismo , Obesidad/metabolismo , Células Asesinas NaturalesRESUMEN
One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.
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Carcinoma Ductal Pancreático , Quinurenina , Neoplasias Pancreáticas , ARN Largo no Codificante , Humanos , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Quinurenina/genética , Quinurenina/metabolismo , Neoplasias Pancreáticas/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMEN
CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.
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Anticuerpos Monoclonales , Neoplasias , Humanos , Unión Proteica , Anticuerpos Monoclonales/efectos adversos , Fatiga , Cefalea , Neoplasias/tratamiento farmacológico , Antígeno CD47RESUMEN
Median survival of patients with glioblastoma (GBM) treated with standard of care which consists of maximal safe resection of the contrast-enhancing portion of the tumor followed by radiation therapy with concomitant adjuvant temozolomide (TMZ) remains 15 months. The tumor microenvironment (TME) is known to contain immune suppressive myeloid cells with minimal effector T cell infiltration. Stimulator of interferon genes (STING) is an important activator of immune response and results in production of Type 1 interferon and antigen presentation by myeloid cells. This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches in gliomas.
Asunto(s)
Glioma , Proteínas de la Membrana , Humanos , Glioma/tratamiento farmacológico , Interferones , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Microambiente TumoralRESUMEN
Therapeutic monoclonal antibodies directed against PD-L1 (e.g., atezolizumab) disrupt PD-L1:PD-1 signaling and reactivate exhausted cytotoxic T-cells in the tumor compartment. Although anti-PD-L1 antibodies are successful as immune checkpoint inhibitor (ICI) therapeutics, there is still a pressing need to develop high-affinity, low-molecular-weight ligands for molecular imaging and diagnostic applications. Affibodies are small polypeptides (â¼60 amino acids) that provide a stable molecular scaffold from which to evolve high-affinity ligands. Despite its proven utility in the development of imaging probes, this scaffold has never been optimized for use in mRNA display, a powerful in vitro selection platform incorporating high library diversity, unnatural amino acids, and chemical modification. In this manuscript, we describe the selection of a PD-L1-binding affibody by mRNA display. Following randomization of the 13 amino acids that define the binding interface of the well-described Her2 affibody, the resulting library was selected against recombinant human PD-L1 (hPD-L1). After four rounds, the enriched library was split and selected against either hPD-L1 or the mouse ortholog (mPD-L1). The dual target selection resulted in the identification of a human/mouse cross-reactive PD-L1 affibody (M1) with low nanomolar affinity for both targets. The M1 affibody bound with similar affinity to mPD-L1 and hPD-L1 expressed on the cell surface and inhibited signaling through the PD-L1:PD-1 axis at low micromolar concentrations in a cell-based functional assay. In vivo optical imaging with M1-Cy5 in an immune-competent mouse model of lymphoma revealed significant tumor uptake relative to a Cy5-conjugated Her2 affibody.