RESUMO
Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-ß signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.
Assuntos
Antígenos CD36/imunologia , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/imunologia , Antígenos CD36/deficiência , Antígenos CD36/genética , Linhagem Celular Tumoral , Feminino , Homeostase/imunologia , Humanos , Imunoterapia , Metabolismo dos Lipídeos/genética , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/metabolismo , Neoplasias/patologia , PPAR beta/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral/imunologiaRESUMO
Neutrophils are critical innate immune cells for the host anti-bacterial defense. Throughout their lifecycle, neutrophils are exposed to different microenvironments and modulate their metabolism to survive and sustain their functions. Although tumor cell metabolism has been intensively investigated, how neutrophil metabolism is affected in cancer remains largely to be discovered. Neutrophils are described as mainly glycolytic cells. However, distinct tumor-associated neutrophil (TAN) states may co-exist in tumors and adapt their metabolism to exert different or even opposing activities ranging from tumor cell killing to tumor support. In this review, we gather evidence about the metabolic mechanisms that underly TANs' pro- or anti-tumoral functions in cancer. We first discuss how tumor-secreted factors and the heterogenous tumor microenvironment can have a strong impact on TAN metabolism. We then describe alternative metabolic pathways used by TANs to exert their functions in cancer, from basic glycolysis to more recently-recognized but less understood metabolic shifts toward mitochondrial oxidative metabolism, lipid and amino acid metabolism and even autophagy. Last, we discuss promising strategies targeting neutrophil metabolism to combat cancer.
Assuntos
Neoplasias , Neutrófilos , Humanos , Redes e Vias Metabólicas , Microambiente TumoralRESUMO
Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress.
Assuntos
Caspase 2/fisiologia , Cisteína Endopeptidases/fisiologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Transporte/fisiologia , Caspase 2/metabolismo , Cisplatino/farmacologia , Cisteína Endopeptidases/metabolismo , Dano ao DNA , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte , Retroalimentação Fisiológica , HumanosRESUMO
Upon detection of viral RNA, the helicases RIG-I and/or MDA5 trigger, via their adaptor Cardif (also known as IPS-1, MAVS, or VISA), the activation of the transcription factors NF-kappaB and IRF3, which collaborate to induce an antiviral type I interferon (IFN) response. FADD and RIP1, known as mediators of death-receptor signaling, are implicated in this antiviral pathway; however, the link between death-receptor and antiviral signaling is not known. Here we showed that TRADD, a crucial adaptor of tumor necrosis factor receptor (TNFRI), was important in RIG-like helicase (RLH)-mediated signal transduction. TRADD is recruited to Cardif and orchestrated complex formation with the E3 ubiquitin ligase TRAF3 and TANK and with FADD and RIP1, leading to the activation of IRF3 and NF-kappaB. Loss of TRADD prevented Cardif-dependent activation of IFN-beta, reduced the production of IFN-beta in response to RNA viruses, and enhanced vesicular stomatitis virus replication. Thus, TRADD is not only an essential component of proinflammatory TNFRI signaling, but is also required for RLH-Cardif-dependent antiviral immune responses.
Assuntos
DNA Helicases/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Infecções por Rhabdoviridae/imunologia , Proteína de Domínio de Morte Associada a Receptor de TNF/metabolismo , Vesiculovirus/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteína de Domínio de Morte Associada a Fas/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Fator Regulador 3 de Interferon/imunologia , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Mutantes , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Superfície Celular , Infecções por Rhabdoviridae/virologia , Transdução de Sinais , Fator 3 Associado a Receptor de TNF/imunologia , Fator 3 Associado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Vesiculovirus/fisiologiaRESUMO
NF-kappaB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-kappaB signalling during the past twenty years, the requirement for NF-kappaB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-kappaB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-kappaB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappaB inhibition. Furthermore, the inhibition of NF-kappaB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-kappaB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-kappaB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Modelos Animais de Doenças , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Células Cultivadas , DNA/metabolismo , Fibroblastos , Genes p53/genética , Humanos , Camundongos , NF-kappa B/antagonistas & inibidores , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/metabolismo , Fator de Transcrição RelA/metabolismo , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
Assuntos
Genes ras/genética , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Alelos , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Perfilação da Expressão Gênica , Genes Letais , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-rel/metabolismo , Transdução de Sinais , Proteína bcl-X/metabolismoRESUMO
Elevated peripheral blood and tumor-infiltrating neutrophils are often associated with a poor patient prognosis. However, therapeutic strategies to target these cells are difficult to implement due to the life-threatening risk of neutropenia. In a genetically engineered mouse model of lung adenocarcinoma, tumor-associated neutrophils (TAN) demonstrate tumor-supportive capacities and have a prolonged lifespan compared to circulating neutrophils. Here, we show that tumor cell-derived GM-CSF triggers the expression of the anti-apoptotic Bcl-xL protein and enhances neutrophil survival through JAK/STAT signaling. Targeting Bcl-xL activity with a specific BH3 mimetic, A-1331852, blocked the induced neutrophil survival without impacting their normal lifespan. Specifically, oral administration with A-1331852 decreased TAN survival and abundance, and reduced tumor growth without causing neutropenia. We also show that G-CSF, a drug used to combat neutropenia in patients receiving chemotherapy, increased the proportion of young TANs and augmented the anti-tumor effect resulting from Bcl-xL blockade. Finally, our human tumor data indicate the same role for Bcl-xL on pro-tumoral neutrophil survival. These results altogether provide preclinical evidence for safe neutrophil targeting based on their aberrant intra-tumor longevity.
Assuntos
Neoplasias Pulmonares , Neutropenia , Animais , Humanos , Camundongos , Envelhecimento , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Proteína bcl-X , Linhagem Celular Tumoral , Neoplasias Pulmonares/patologia , Neutropenia/tratamento farmacológico , Neutropenia/metabolismo , Neutropenia/patologia , Neutrófilos/metabolismoRESUMO
PURPOSE OF REVIEW: The review aims at comprehensively discussing our current knowledge on bone metastases incidence in non-small cell lung cancer (NSCLC), their related complications as well as clinical impact in patients suffering from advanced disease. RECENT FINDINGS: After evoking the use of zoledronic acid as the established standard of care until recently, the new class of drugs available to prevent skeletal related events and targeting receptor activator of nuclear factor-kappa B (RANK) will be emphasized, reporting on denosumab clinical trials, a RANK-ligand (RANKL) targeting monoclonal antibody. Biological hypothesis regarding their mechanisms of action as well a potential direct impact on tumor cells are described according to the most recent laboratory as well as hypothesis-generating clinical data. SUMMARY: Targeting the RANK pathway is an efficient way to prevent complications of bone metastases in NSCLC. Interesting additional direct effects on tumor biology and evolution are being analyzed and prospectively assessed in clinical trials.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Receptor Ativador de Fator Nuclear kappa-B/antagonistas & inibidores , Neoplasias Ósseas/secundário , Ensaios Clínicos como Assunto , HumanosRESUMO
Despite advances in targeted therapies and immunotherapy in lung cancer, chemotherapy remains the backbone of treatment in most patients at different stages of the disease. Inhaled chemotherapy is a promising strategy to target lung tumours and to limit the induced severe systemic toxicities. Cisplatin dry powder for inhalation (CIS-DPI) was tested as an innovative way to deliver cisplatin locally via the pulmonary route with minimal systemic toxicities. In vivo, CIS-DPI demonstrated a dose-dependent antiproliferative activity in the M109 orthotopic murine lung tumour model and upregulated the immune checkpoint PD-L1 on lung tumour cells. Combination of CIS-DPI with the immune checkpoint inhibitor anti-PD1 showed significantly reduced tumour size, increased the number of responders and prolonged median survival over time in comparison to the anti-PD1 monotherapy. Furthermore, the CIS-DPI and anti-PD1 combination induced an intra-tumour recruitment of conventional dendritic cells and tumour infiltrating lymphocytes, highlighting an anti-tumour immune response. This study demonstrates that combining CIS-DPI with anti-PD1 is a promising strategy to improve lung cancer therapy.
Assuntos
Cisplatino , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Cisplatino/uso terapêutico , Pós , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pulmão/patologia , ImunidadeRESUMO
The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and eliminate them. Indeed, Toll-like receptors are a class of membrane receptors that sense extracellular microbes and trigger anti-pathogen signalling cascades. Recently, intracellular microbial sensors have also been identified, including NOD-like receptors and the helicase-domain-containing antiviral proteins RIG-I and MDA5. Some of these cytoplasmic molecules sense microbial, as well as non-microbial, danger signals, but the mechanisms of recognition used by these sensors remain poorly understood. Nonetheless, it is apparent that these proteins are likely to have critical roles in health and disease.
Assuntos
Imunidade Inata/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Humanos , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , RNA Viral/imunologiaRESUMO
BACKGROUND: Activin-A, a transforming growth factor ß family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have shown that Activin-A expression can promote cancer progression and reduce the intratumoral frequency of cytotoxic T cells. However, the underlying mechanisms and the significance of Activin-A expression for cancer therapies are unclear. METHODS: We analyzed the expression of the Activin-A encoding gene INHBA in melanoma patients and the influence of its gain- or loss-of-function on the immune infiltration and growth of BRAF-driven YUMM3.3 and iBIP2 mouse melanoma grafts and in B16 models. Using antibody depletion strategies, we investigated the dependence of Activin-A tumor-promoting effect on different immune cells. Immune-regulatory effects of Activin-A were further characterized in vitro and by an adoptive transfer of T cells. Finally, we assessed INHBA expression in melanoma patients who received immune checkpoint therapy and tested whether it impairs the response in preclinical models. RESULTS: We show that Activin-A secretion by melanoma cells inhibits adaptive antitumor immunity irrespective of BRAF status by inhibiting CD8+ T cell infiltration indirectly and even independently of CD4 T cells, at least in part by attenuating the production of CXCL9/10 by myeloid cells. In addition, we show that Activin-A/INHBA expression correlates with anti-PD1 therapy resistance in melanoma patients and impairs the response to dual anti-cytotoxic T-Lymphocyte associated protein 4/anti-PD1 treatment in preclinical models. CONCLUSIONS: Our findings suggest that strategies interfering with Activin-A induced immune-regulation offer new therapeutic opportunities to overcome CD8 T cell exclusion and immunotherapy resistance.
Assuntos
Ativinas , Melanoma , Ativinas/metabolismo , Ativinas/uso terapêutico , Animais , Linfócitos T CD8-Positivos , Humanos , Imunidade Celular , Subunidades beta de Inibinas , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/imunologia , Camundongos , Proteínas Proto-Oncogênicas B-raf/metabolismoRESUMO
Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation. We address discrepancies in the literature that highlight a need for technical standards that ought to be considered between laboratories. Finally, we review emerging questions in neutrophil biology and innate immunity in cancer. Overall, we emphasize that neutrophils are a more diverse population than previously appreciated and that their role in cancer may present novel unexplored opportunities to treat cancer.
Assuntos
Neoplasias , Neutrófilos , Humanos , Imunidade Inata , Inflamação , Neoplasias/genética , FenótipoRESUMO
Hepatitis C virus (HCV) infection induces the endogenous interferon (IFN) system in the liver in some but not all patients with chronic hepatitis C (CHC). Patients with a pre-activated IFN system are less likely to respond to the current standard therapy with pegylated IFN-alpha. Mitochondrial antiviral signaling protein (MAVS) is an important adaptor molecule in a signal transduction pathway that senses viral infections and transcriptionally activates IFN-beta. The HCV NS3-4A protease can cleave and thereby inactivate MAVS in vitro, and, therefore, might be crucial in determining the activation status of the IFN system in the liver of infected patients. We analyzed liver biopsies from 129 patients with CHC to investigate whether MAVS is cleaved in vivo and whether cleavage prevents the induction of the endogenous IFN system. Cleavage of MAVS was detected in 62 of the 129 samples (48%) and was more extensive in patients with a high HCV viral load. MAVS was cleaved by all HCV genotypes (GTs), but more efficiently by GTs 2 and 3 than by GTs 1 and 4. The IFN-induced Janus kinase (Jak)-signal transducer and activator of transcription protein (STAT) pathway was less frequently activated in patients with cleaved MAVS, and there was a significant inverse correlation between cleavage of MAVS and the expression level of the IFN-stimulated genes IFI44L, Viperin, IFI27, USP18, and STAT1. We conclude that the pre-activation status of the endogenous IFN system in the liver of patients with CHC is in part regulated by cleavage of MAVS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Hepatite C Crônica/metabolismo , Interferons/metabolismo , Fígado/metabolismo , Linhagem Celular , Hepatite C Crônica/virologia , Humanos , Carga ViralRESUMO
Detection of viral nucleic acids is central to antiviral immunity. Recently, DAI/ZBP1 (DNA-dependent activator of IRFs/Z-DNA binding protein 1) was identified as a cytoplasmic DNA sensor and shown to activate the interferon regulatory factor (IRF) and nuclear factor-kappa B (NF-kappaB) transcription factors, leading to type-I interferon production. DAI-induced IRF activation depends on TANK-binding kinase 1 (TBK1), whereas signalling pathways and molecular components involved in NF-kappaB activation remain elusive. Here, we report the identification of two receptor-interacting protein (RIP) homotypic interaction motifs (RHIMs) in the DAI protein sequence, and show that these domains relay DAI-induced NF-kappaB signals through the recruitment of the RHIM-containing kinases RIP1 and RIP3. We show that knockdown of not only RIP1, but also RIP3 affects DAI-induced NF-kappaB activation. Importantly, RIP recruitment to DAI is inhibited by the RHIM-containing murine cytomegalovirus (MCMV) protein M45. These findings delineate the DAI signalling pathway to NF-kappaB and suggest a possible new immune modulation strategy of the MCMV.
Assuntos
Proteínas de Ligação a DNA/metabolismo , NF-kappa B/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/química , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Proteínas de Ligação a DNA/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Immunoblotting , Imunoprecipitação , Camundongos , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Reação em Cadeia da Polimerase , Ligação Proteica/genética , Ligação Proteica/fisiologia , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Proteína Serina-Treonina Quinases de Interação com Receptores/genéticaRESUMO
Antiviral immunity against a pathogen is mounted upon recognition by the host of virally associated structures. One of these viral 'signatures', double-stranded (ds) RNA, is a replication product of most viruses within infected cells and is sensed by Toll-like receptor 3 (TLR3) and the recently identified cytosolic RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5, also known as Ifih1 or Helicard). Both helicases detect dsRNA, and through their protein-interacting CARD domains, relay an undefined signal resulting in the activation of the transcription factors interferon regulatory factor 3 (IRF3) and NF-kappaB. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKalpha, IKKbeta and IKKvarepsilon kinases by means of its C-terminal region, leading to the activation of NF-kappaB and IRF3. Overexpression of Cardif results in interferon-beta and NF-kappaB promoter activation, and knockdown of Cardif by short interfering RNA inhibits RIG-I-dependent antiviral responses. Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-beta production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antivirais/metabolismo , Hepacivirus/metabolismo , RNA Helicases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Animais , Antivirais/imunologia , Linhagem Celular , Proteína DEAD-box 58 , RNA Helicases DEAD-box , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Hepacivirus/enzimologia , Hepacivirus/imunologia , Humanos , Quinase I-kappa B , Fator Regulador 3 de Interferon , Interferon beta/biossíntese , Interferon beta/genética , Interferon beta/imunologia , Camundongos , Dados de Sequência Molecular , NF-kappa B/metabolismo , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , RNA Helicases/imunologia , Receptores Imunológicos , Especificidade por Substrato , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas não Estruturais Virais/metabolismoRESUMO
The immune checkpoint blockade-based immunotherapies are revolutionizing cancer management. Tumor-associated neutrophils (TANs) were recently highlighted to have a pivotal role in modulating the tumor microenvironment and the antitumor immune response. However, these cells were largely ignored during the development of therapies based on programmed cell death receptor or ligand-1 and cytotoxic T lymphocyte antigen-4 immune checkpoint inhibitors (ICIs). Latest evidences of neutrophil functional diversity in tumor raised many questions and suggest that targeting these cells can offer new treatment opportunities in the context of ICI development. Here, we summarized key information on TAN origin, function, and plasticity that should be considered when developing ICIs and provide a detailed review of the ongoing clinical trials that combine ICIs and a second compound that might affect or be affected by TANs. This review article synthetizes important notions from the literature demonstrating that: (1) Cancer development associates with a profound alteration of neutrophil biogenesis and function that can predict and interfere with the response to ICIs, (2) Neutrophil infiltration in tumor is associated with key features of resistance to ICIs, and (3) TANs play an important role in resistance to antiangiogenic drugs reducing their clinical benefit when used in combination with ICIs. Finally, exploring the clinical/translational aspects of neutrophil impact on the response to ICIs offers the opportunity to propose new translational research avenues to better understand TAN biology and treat patients.
Assuntos
Inibidores de Checkpoint Imunológico/sangue , Neutrófilos/metabolismo , HumanosRESUMO
Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of Kras G12D/+;p53 -/- NSCLC, including a mismatch repair-deficient variant (Kras G12D/+;p53 -/-;Msh2 -/-) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy. Antiangiogenic blockade of vascular endothelial growth factor A and angiopoietin-2 markedly slowed progression of autochthonous lung tumors, but contrary to findings in other cancer types, addition of a PD-1 or PD-L1 antibody was not beneficial and even accelerated progression of a fraction of the tumors. We found that antiangiogenic treatment facilitated tumor infiltration by PD-1+ regulatory T cells (Tregs), which were more efficiently targeted by the PD-1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of monocyte origin, which are colony-stimulating factor 1 receptor (CSF1R) dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establish a transforming growth factor-ß-rich tumor microenvironment that supported PD-1+ Tregs Dual TAM targeting with a combination of a CSF1R inhibitor and cisplatin abated Tregs, redirected the PD-1 antibody to CD8+ T cells, and improved the efficacy of antiangiogenic immunotherapy, achieving regression of most tumors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Antígeno B7-H1 , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Receptor de Morte Celular Programada 1 , Microambiente Tumoral , Fator A de Crescimento do Endotélio VascularRESUMO
The anti-Ly6G antibody is used to deplete Ly6Gpos neutrophils and study their role in diverse pathologies. However, depletion is never absolute, as Ly6Glow neutrophils resistant to depletion rapidly emerge. Studying the functionality of these residual neutrophils is necessary to interpret anti-Ly6G-based experimental designs. In vitro, we found anti-Ly6G binding induced Ly6G internalization, surface Ly6G paucity, and primed the oxidative burst of neutrophils upon TNF α co-stimulation. In vivo, we found neutrophils resistant to anti-Ly6G depletion exhibited anti-neutrophil-cytoplasmic-antibodies. In the pre-clinical KrasLox-STOP-Lox-G12D/WT; Trp53Flox/Flox mouse lung tumor model, abnormal neutrophil accumulation and aging was accompanied with an N2-like SiglecFpos polarization and ly6g downregulation. Consequently, SiglecFpos neutrophils exposed to anti-Ly6G reverted to Ly6Glow and were resistant to depletion. Noting that anti-Ly6G mediated neutrophil depletion alone had no anti-tumor effect, we found a long-lasting rate of tumor regression (50%) by combining anti-Ly6G with radiation-therapy, in this model reputed to be refractory to standard anticancer therapies. Mechanistically, anti-Ly6G regulated neutrophil aging while radiation-therapy enhanced the homing of anti-Ly6G-boundSiglecFneg neutrophils to tumors. This anti-tumor effect was recapitulated by G-CSF administration prior to RT and abrogated with an anti-TNFα antibody co-administration. In summary, we report that incomplete depletion of neutrophils using targeted antibodies can intrinsically promote their oxidative activity. This effect depends on antigen/antibody trafficking and can be harnessed locally using select delivery of radiation-therapy to impair tumor progression. This underutilized aspect of immune physiology may be adapted to expand the scope of neutrophil-related research.
Assuntos
Antígenos Ly , Neutrófilos , Animais , Anticorpos Anticitoplasma de Neutrófilos , Modelos Animais de Doenças , Camundongos , Inibidores do Fator de Necrose TumoralRESUMO
Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils. SIGNIFICANCE: Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2345/F1.large.jpg.