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1.
Proc Natl Acad Sci U S A ; 117(1): 541-551, 2020 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-31889004

RESUMEN

Cancer immunotherapies are increasingly combined with targeted therapies to improve therapeutic outcomes. We show that combination of agonistic anti-CD40 with antiangiogenic antibodies targeting 2 proangiogenic factors, vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (Ang2/ANGPT2), induces pleiotropic immune mechanisms that facilitate tumor rejection in several tumor models. On the one hand, VEGFA/Ang2 blockade induced regression of the tumor microvasculature while decreasing the proportion of nonperfused vessels and reducing leakiness of the remaining vessels. On the other hand, both anti-VEGFA/Ang2 and anti-CD40 independently promoted proinflammatory macrophage skewing and increased dendritic cell activation in the tumor microenvironment, which were further amplified upon combination of the 2 treatments. Finally, combined therapy provoked brisk infiltration and intratumoral redistribution of cytotoxic CD8+ T cells in the tumors, which was mainly driven by Ang2 blockade. Overall, these nonredundant synergistic mechanisms endowed T cells with improved effector functions that were conducive to more efficient tumor control, underscoring the therapeutic potential of antiangiogenic immunotherapy in cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígenos CD40/agonistas , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Angiopoyetina 2/antagonistas & inhibidores , Angiopoyetina 2/metabolismo , Animales , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígenos CD40/inmunología , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Neoplasias/irrigación sanguínea , Neoplasias/inmunología , Neoplasias/patología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/inmunología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo
2.
Cancer Immunol Immunother ; 67(5): 815-824, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29487979

RESUMEN

Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi-receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies. In different syngeneic murine tumor models, axitinib showed therapeutic efficacy that was not only mediated by VEGF-VEGFR inhibition, but also through the induction of anti-cancer immunity. Mechanistically, a significant reduction of immune-suppressive cells, including a decrease of tumor-promoting mast cells and tumor-associated macrophages was observed upon axitinib treatment. Inhibition of mast cells by axitinib as well as their experimental depletion led to reduced tumor growth. Of note, treatment with axitinib led to an improved T cell response, while the latter was pivotal for the therapeutic efficacy. Combination with immune checkpoint inhibitors anti-PD-1 and anti-TIM-3 and/or agonistic engagement of the activating receptor CD137 resulted in a synergistic therapeutic efficacy. This demonstrates non-redundant immune activation induced by axitinib via modulation of myeloid and mast cells. These findings provide important mechanistic insights into axitinib-mediated anti-cancer immunity and provide rationale for clinical combinations of axitinib with different immunotherapeutic modalities.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Sinergismo Farmacológico , Imidazoles/farmacología , Terapia de Inmunosupresión , Indazoles/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Axitinib , Carcinoma Pulmonar de Lewis/inmunología , Carcinoma Pulmonar de Lewis/patología , Modelos Animales de Enfermedad , Receptor 2 Celular del Virus de la Hepatitis A/antagonistas & inhibidores , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Inmunoterapia , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Células Tumorales Cultivadas , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/antagonistas & inhibidores , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
3.
J Immunother Cancer ; 11(5)2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37208130

RESUMEN

BACKGROUND: Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy. METHODS: We designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor. RESULTS: IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development. CONCLUSIONS: By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.


Asunto(s)
Neoplasias , Receptor Toll-Like 9 , Humanos , Ratones , Animales , Receptor Toll-Like 9/metabolismo , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Oligonucleótidos Antisentido , Células Dendríticas
4.
Nat Commun ; 14(1): 86, 2023 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-36732507

RESUMEN

Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca2+, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.


Asunto(s)
Neoplasias , Agotamiento de Células T , Humanos , Linfocitos T CD8-positivos , Inmunoterapia , Linfocitos Infiltrantes de Tumor
5.
Sci Transl Med ; 14(653): eabm9043, 2022 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-35857639

RESUMEN

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)-interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5-IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5-IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a+ NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5-IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ-inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a+ CXCR6+ NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance.


Asunto(s)
Integrina alfa1 , Neoplasias , Animales , Células Dendríticas , Inmunoterapia , Integrina alfa1/metabolismo , Interleucina-12/metabolismo , Células Asesinas Naturales , Ratones , Neoplasias/patología , Receptor de Muerte Celular Programada 1/metabolismo , Microambiente Tumoral
6.
Front Oncol ; 11: 644608, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33747968

RESUMEN

Reprogramming tumor infiltrating myeloid cells to elicit pro-inflammatory responses is an exciting therapeutic maneouver to improve anti-tumor responses. We recently demonstrated that a distinct microtubule-targeting drug, plinabulin-a clinical-stage novel agent-modulates dendritic cell maturation and enhances anti-tumor immunity. Here, we investigated the effects of plinabulin on macrophage polarization in vitro and in vivo. Plinabulin monotherapy induced significant tumor growth inhibition in mice bearing subcutaneous MC38 colon cancer. Importantly, the regressing tumors were characterized by an increase in M1-like/M2-like tumor-associated macrophages (TAM) ratio. The efficacy of plinabulin remained unaltered in T cell-deficient Rag2-/- mice, suggesting an important role of macrophages in driving the drug's anti-tumor effect. Exposure of murine and healthy human macrophages to plinabulin induced polarization toward the M1 phenotype, including increased expression of co-stimulatory molecules CD80, CD86 and pro-inflammatory cytokines IL-1ß, IL-6, and IL-12. M2-associated immunosuppressive cytokines IL-10 and IL-4 were reduced. This pro-inflammatory M1-like skewing of TAMs in response to plinabulin was dependent on the JNK pathway. Functionally, plinabulin-polarized human M1 macrophages directly killed HuT 78 tumor cells in vitro. Importantly, plinabulin induced a functional M1-like polarization of tumor infiltrating macrophages in murine tumors as well as in tumor samples from ovarian cancer patients, by preferentially triggering M1 proliferation. Our study uncovers a novel immunomodulatory effect of plinabulin in directly triggering M1 polarization and proliferation as well as promoting TAM anti-tumoral effector functions.

7.
J Immunother Cancer ; 7(1): 67, 2019 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-30871609

RESUMEN

BACKGROUND: Cancer cells are known to develop mechanisms to circumvent effective anti-tumor immunity. The two ectonucleotidases CD39 and CD73 are promising drug targets, as they act in concert to convert extracellular immune-stimulating ATP to adenosine. CD39 is expressed by different immune cell populations as well as cancer cells of different tumor types and supports the tumor in escaping immune recognition and destruction. Thus, increasing extracellular ATP and simultaneously reducing adenosine concentrations in the tumor can lead to effective anti-tumor immunity. METHODS: We designed locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) with specificity for human or mouse CD39 that do not need a transfection reagent or delivery system for efficient target knockdown. Knockdown efficacy of ASOs on mRNA and protein level was investigated in cancer cell lines and in primary human T cells. The effect of CD39 knockdown on ATP-degrading activity was evaluated by measuring levels of ATP in tumor cell supernatants and analysis of T cell proliferation in the presence of extracellular ATP. The in vivo effects of CD39-specific ASOs on target expression, anti-tumor immune responses and on tumor growth were analyzed in syngeneic mouse tumor models using multi-color flow cytometry. RESULTS: CD39-specific ASOs suppressed expression of CD39 mRNA and protein in different murine and human cancer cell lines and in primary human T cells. Degradation of extracellular ATP was strongly reduced by CD39-specific ASOs. Strikingly, CD39 knockdown by ASOs was associated with improved CD8+ T cell proliferation. Treatment of tumor-bearing mice with CD39-specific ASOs led to dose-dependent reduction of CD39-protein expression in regulatory T cells (Tregs) and tumor-associated macrophages. Moreover, frequency of intratumoral Tregs was substantially reduced in CD39 ASO-treated mice. As a consequence, the ratio of CD8+ T cells to Tregs in tumors was improved, while PD-1 expression was induced in CD39 ASO-treated intratumoral CD8+ T cells. Consequently, CD39 ASO treatment demonstrated potent reduction in tumor growth in combination with anti-PD-1 treatment. CONCLUSION: Targeting of CD39 by ASOs represents a promising state-of-the art therapeutic approach to improve immune responses against tumors.


Asunto(s)
Apirasa/genética , Silenciador del Gen , Inmunidad/genética , Neoplasias/genética , Neoplasias/inmunología , Oligonucleótidos Antisentido/genética , Adenosina/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos Inmunológicos/farmacología , Biomarcadores de Tumor , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Neoplasias/patología , Oligonucleótidos Antisentido/administración & dosificación , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
8.
J Immunother Cancer ; 7(1): 16, 2019 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-30665463

RESUMEN

Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU) in a human HER2-expressing syngeneic breast cancer model resistant to trastuzumab and ado-trastuzumab emtansine. Mechanistically, the anthracycline component of the novel ADC induced immunogenic cell death leading to exposure and secretion of danger-associated molecular signals. RNA sequencing derived immunogenomic signatures and TCRß clonotype analysis of tumor-infiltrating lymphocytes revealed a prominent role of the adaptive immune system in the regulation of T-PNU mediated anti-cancer activity. Depletion of CD8 T cells severely reduced T-PNU efficacy, thus confirming the role of cytotoxic T cells as drivers of the T-PNU mediated anti-tumor immune response. Furthermore, T-PNU therapy promoted immunological memory formation in tumor-bearing animals protecting those from tumor rechallenge. Finally, the combination of T-PNU and checkpoint inhibition, such as α-PD1, significantly enhanced tumor eradication following the treatment. In summary, a novel PNU-armed, HER2-targeting ADC elicited long-lasting immune protection in a murine orthotopic breast cancer model resistant to other HER2-directed therapies. Our findings delineate the therapeutic potential of this novel ADC payload and support its clinical development for breast cancer patients and potentially other HER2 expressing malignancies.


Asunto(s)
Antraciclinas/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Inmunoconjugados/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Femenino , Humanos , Memoria Inmunológica/efectos de los fármacos , Neoplasias Mamarias Experimentales/inmunología , Ratones Endogámicos BALB C , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico
9.
Curr Biol ; 23(1): 11-20, 2013 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-23177478

RESUMEN

BACKGROUND: Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species, but not competitors of closely related species. This implies rapid evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown. RESULTS: Here, we identify a mouse chemosignal, trimethylamine, and its olfactory receptor, trace amine-associated receptor 5 (TAAR5), to be involved in species-specific social communication. Abundant (>1,000-fold increased) and sex-dependent trimethylamine production arose de novo along the Mus lineage after divergence from Mus caroli. The two-step trimethylamine biosynthesis pathway involves synergy between commensal microflora and a sex-dependent liver enzyme, flavin-containing monooxygenase 3 (FMO3), which oxidizes trimethylamine. One key evolutionary alteration in this pathway is the recent acquisition in Mus of male-specific Fmo3 gene repression. Coincident with its evolving biosynthesis, trimethylamine evokes species-specific behaviors, attracting mice, but repelling rats. Attraction to trimethylamine is abolished in TAAR5 knockout mice, and furthermore, attraction to mouse scent is impaired by enzymatic depletion of trimethylamine or TAAR5 knockout. CONCLUSIONS: TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions.


Asunto(s)
Conducta Animal , Evolución Biológica , Metilaminas/metabolismo , Odorantes , Olfato/fisiología , Animales , Femenino , Masculino , Metilaminas/orina , Ratones , Ratones Noqueados , Resonancia Magnética Nuclear Biomolecular , Oxigenasas/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Factores Sexuales , Especificidad de la Especie , Orina/química
10.
Behav Brain Res ; 222(2): 397-400, 2011 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-21510981

RESUMEN

Orexin-deficient mice are an established animal model for narcolepsy. In human patients, narcoleptic events are mainly triggered by emotional events. However, the role of emotional stimuli in murine narcolepsy is not well understood. The present study investigated the effects of attractive and aversive odor stimuli, i.e., urine samples of coyote and female mice, on narcoleptic episodes (cataplexy, sleep attacks) in orexin-deficient mice. Here, we first demonstrate that exposure to both attractive and aversive odors significantly increase the number of narcoleptic episodes in orexin-deficient mice. This behavioral paradigm may be of high interest for studies focused on the question how emotions can trigger narcoleptic episodes.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/fisiología , Narcolepsia/fisiopatología , Narcolepsia/psicología , Neuropéptidos/deficiencia , Neuropéptidos/fisiología , Percepción Olfatoria/fisiología , Animales , Coyotes/orina , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Ratones Endogámicos C57BL/orina , Ratones Noqueados , Narcolepsia/inducido químicamente , Neuropéptidos/genética , Odorantes , Orexinas
11.
Behav Brain Res ; 217(1): 1-9, 2011 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-20888368

RESUMEN

The present study investigated the phenotype of heterozygous and homozygous neuropeptide S receptor (Npsr) deficient C57BL/6 mice in NPS- and cocaine induced hyperactivity, spontaneous and reactive locomotor activity, elevated plus maze, conditioned fear, and prepulse inhibition of the acoustic startle response. In Npsr-deficient mice, a strong reduction of spontaneous locomotor activity and of the startle magnitude was observed; heterozygous mice had an intermediate phenotype. In the other experiments, Npsr deficiency leads to no or only a very modest phenotype. These results support an important role of neuropeptide S in regulating locomotor activity.


Asunto(s)
Actividad Motora/genética , Receptores Acoplados a Proteínas G/fisiología , Reflejo de Sobresalto/genética , Estimulación Acústica , Animales , Cocaína/administración & dosificación , Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Pérdida de Tono Postural/efectos de los fármacos , Pérdida de Tono Postural/fisiología , Infusiones Intraventriculares , Inhibición Psicológica , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuropéptidos/administración & dosificación , Neuropéptidos/farmacología , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Acoplados a Proteínas G/genética , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología
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