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1.
Oncoimmunology ; 10(1): 1863631, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33643689

RESUMO

We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8-45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov).

2.
Cell Rep ; 32(9): 108080, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877684

RESUMO

The DNA-dependent pattern recognition receptor, cGAS (cyclic GMP-AMP synthase), mediates communication between the DNA damage and the immune responses. Mitotic chromosome missegregation stimulates cGAS activity; however, it is unclear whether progression through mitosis is required for cancercell-intrinsic activation of anti-tumor immune responses. Moreover, it is unknown whether cell cycle checkpoint disruption can restore responses in cancer cells that are recalcitrant to DNAdamage-induced inflammation. Here, we demonstrate that prolonged cell cycle arrest at the G2-mitosis boundary from either excessive DNA damage or CDK1 inhibition prevents inflammatory-stimulated gene expression and immune-mediated destruction of distal tumors. Remarkably, DNAdamage-induced inflammatory signaling is restored in a RIG-I-dependent manner upon concomitant disruption of p53 and the G2 checkpoint. These findings link aberrant cell progression and p53 loss to an expanded spectrum of damage-associated molecular pattern recognition and have implications for the design of rational approaches to augment anti-tumor immune responses.

3.
Semin Radiat Oncol ; 30(2): 173-180, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32381296

RESUMO

Immune checkpoint inhibitors have shown remarkable clinical benefit across a variety of cancer types. However, the majority of patients do not respond or develop relapse after therapy. Radiation can favorably modulate the immune system and enhance tumor antigen recognition and rejection. Thus, the combination of radiation and immune checkpoint blockade (ICB) has been recognized as a promising strategy to improve tumor response and broaden the clinical utility of immunotherapy. In this review, we highlight the preclinical and clinical experience at our institution aimed at understanding and promoting the immunostimulatory effect of radiation. We discuss the rationale, design, results, and lessons from our clinical trials in combining radiation with anti-CTLA4 and/or anti-PD-1 therapy. In parallel, our studies to understand the resistance mechanism to radiation and ICB have converged on interferon (IFN) signaling as a key regulatory pathway. Persistent IFN-γ signaling impairs anti-tumor immune responses which can be reversed by using JAK inhibitor to disrupt the IFN signaling. Lastly we discuss remaining challenges, ongoing studies, and future directions in combining radiation with immunotherapy.

4.
Cell ; 178(4): 933-948.e14, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398344

RESUMO

Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, including a PD1+TRAIL+ ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Interferon gama/genética , Interferon gama/metabolismo , Neoplasias Pulmonares/imunologia , Melanoma/imunologia , Transferência Adotiva , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Técnicas de Inativação de Genes , Humanos , Interferon gama/antagonistas & inibidores , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , RNA-Seq , Transfecção
6.
J Immunother Cancer ; 7(1): 131, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31113486

RESUMO

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.


Assuntos
Imunoterapia , Neoplasias/terapia , Microambiente Tumoral/imunologia , Comitês Consultivos , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Congressos como Assunto , Modelos Animais de Doenças , Humanos , Oncologia/organização & administração , Neoplasias/genética , Neoplasias/imunologia , Sociedades Médicas/organização & administração , Resultado do Tratamento , Microambiente Tumoral/genética
7.
Cancer Cell ; 35(1): 33-45.e6, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30645975

RESUMO

Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Low CH25H levels in leukocytes from melanoma patients correlated with poor prognosis. Mice incapable of downregulating the IFN receptor and Ch25h were resistant to TEV uptake, TEV-induced pre-metastatic niche, and melanoma lung metastases; however, ablation of Ch25h reversed these phenotypes. An anti-hypertensive drug, reserpine, suppressed TEV uptake and disrupted TEV-induced formation of the pre-metastatic niche and melanoma lung metastases. These results suggest the importance of CH25H in defense against education of normal cells by TEV and argue for the use of reserpine in adjuvant melanoma therapy.


Assuntos
Vesículas Extracelulares/metabolismo , Neoplasias Pulmonares/secundário , Melanoma/patologia , Receptor de Interferon alfa e beta/metabolismo , Esteroide Hidroxilases/metabolismo , Animais , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Interferons/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Melanoma/metabolismo , Camundongos , Metástase Neoplásica , Oxisteróis/metabolismo , Reserpina/administração & dosagem , Reserpina/farmacologia , Esteroide Hidroxilases/genética , Células THP-1
8.
Br J Cancer ; 119(10): 1200-1207, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30318516

RESUMO

BACKGROUND: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers. METHODS: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response. RESULTS: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells. CONCLUSIONS: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy. CLINICAL TRIAL REGISTRATION: NCT02303990 ( www.clinicaltrials.gov ).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quimiorradioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Melanoma/tratamento farmacológico , Melanoma/radioterapia , Hipofracionamento da Dose de Radiação , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/radioterapia , Neoplasias Cutâneas/patologia
9.
Cancer Res ; 78(15): 4282-4291, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29844122

RESUMO

Immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains a difficult clinical problem despite success in other disease types with immune checkpoint blockade (ICB) and chimeric antigen receptor T-cell therapy. Mechanisms driving immunosuppression and poor T-cell infiltration in PDA are incompletely understood. Here, we use genetically engineered mouse models of PDA that recapitulate hallmarks of human disease to demonstrate that CD40 pathway activation is required for clinical response to radiotherapy and ICB with αCTLA-4 and αPD-1. The combination of an agonist αCD40 antibody, radiotherapy, and dual ICB eradicated irradiated and unirradiated (i.e., abscopal) tumors, generating long-term immunity. Response required T cells and also short-lived myeloid cells and was dependent on the long noncoding RNA myeloid regulator Morrbid Using unbiased random forest machine learning, we built unique, contextual signatures for each therapeutic component, revealing that (i) radiotherapy triggers an early proinflammatory stimulus, ablating existing intratumoral T cells and upregulating MHC class I and CD86 on antigen-presenting cells, (ii) αCD40 causes a systemic and intratumoral reorganization of the myeloid compartment, and (iii) ICB increases intratumoral T-cell infiltration and improves the CD8 T-cell:regulatory T-cell ratio. Thus, αCD40 and radiotherapy nonredundantly augment antitumor immunity in PDA, which is otherwise refractory to ICB, providing a clear rationale for clinical evaluation.Significance: Radiotherapy and αCD40 disrupt key links between innate and adaptive immunity, ameliorating resistance to immune checkpoint blockade in pancreatic cancer via multiple cellular mechanisms. Cancer Res; 78(15); 4282-91. ©2018 AACR.


Assuntos
Antígenos CD40/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/radioterapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/radioterapia , Imunidade Adaptativa/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Feminino , Tolerância Imunológica/imunologia , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/imunologia
10.
Immunity ; 48(3): 417-433, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29562193

RESUMO

The success of immune checkpoint blockade in patients with a wide variety of malignancies has changed the treatment paradigm in oncology. However, combination therapies with immune checkpoint blockade will be needed to overcome resistance and broaden the clinical utility of immunotherapy. Here we discuss a framework for rationally designing combination therapy strategies based on enhancing major discriminatory functions of the immune system that are corrupted by cancer-namely, antigenicity, adjuvanticity, and homeostatic feedback inhibition. We review recent advances on how conventional genotoxic cancer therapies, molecularly targeted therapies, epigenetic agents, and immune checkpoint inhibitors can restore these discriminatory functions. Potential barriers that can impede response despite combination therapy are also discussed.


Assuntos
Imunoterapia , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/terapia , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Terapia Combinada , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
11.
Cancer ; 124(1): 183-191, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28885696

RESUMO

BACKGROUND: Nearly 1 in 5 Americans will develop skin cancer, and as a result, survivors of skin cancer compose one of the largest groups of cancer survivors. Survivorship care plans (SCPs) are an important tool for improving patient outcomes and provide critical information to both survivors and health care professionals. Recent efforts have been made to expand SCP utilization; however, which patients currently receive SCPs is poorly understood. METHODS: This study used 596 individuals with a diagnosis of melanoma (n = 391) or nonmelanoma skin cancer (n = 205) who had used an Internet-based SCP tool from May 2010 to December 2016 to model the patient and provider characteristics that determine SCP utilization. RESULTS: Survivors were predominantly white (95.3%) and female (56.5%). Survivors who received a treatment summary were more likely to also receive an SCP. University and nonuniversity cancer centers used SCPs at a higher rate than other care settings. Survivors whose care was managed by a team rather than just an individual physician were also more likely to receive an SCP. Survivors older than 70 years at diagnosis were almost twice as likely to receive a plan as survivors who were diagnosed at a younger age. CONCLUSIONS: With a convenience sample of skin cancer survivors, it is possible to model factors that predict the receipt of SCPs. Important variables include the diagnosis age, treatment setting, physician type, and treatment-summary utilization. A closer examination of these variables identified several disparities in care-plan use and, therefore, opportunities to improve the distribution of SCPs. Further validation in additional cohorts of survivors is necessary to confirm these conclusions. Cancer 2018;124:183-91. © 2017 American Cancer Society.


Assuntos
Assistência ao Convalescente/métodos , Sobreviventes de Câncer , Melanoma/terapia , Planejamento de Assistência ao Paciente/estatística & dados numéricos , Neoplasias Cutâneas/terapia , Sobrevivência , Centros Médicos Acadêmicos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncologistas , Médicos de Atenção Primária , Aprendizado de Máquina Supervisionado , Estados Unidos
12.
Nature ; 548(7668): 466-470, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28759889

RESUMO

Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumour microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumour responses to radiotherapy. A poorly understood feature of these responses is the delayed onset (days), in contrast to the acute DNA-damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate-limiting steps that are essential for DNA-damage-induced inflammation. Here we show that cell cycle progression through mitosis following double-stranded DNA breaks leads to the formation of micronuclei, which precede activation of inflammatory signalling and are a repository for the pattern-recognition receptor cyclic GMP-AMP synthase (cGAS). Inhibiting progression through mitosis or loss of pattern recognition by stimulator of interferon genes (STING)-cGAS impaired interferon signalling. Moreover, STING loss prevented the regression of abscopal tumours in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.


Assuntos
Dano ao DNA , Inflamação/metabolismo , Micronúcleos com Defeito Cromossômico , Mitose , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais , Animais , Antígeno CTLA-4/antagonistas & inibidores , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/patologia , Interferons/metabolismo , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nucleotidiltransferases/metabolismo
13.
Cell ; 170(2): 352-366.e13, 2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28709002

RESUMO

Interactions between stromal fibroblasts and cancer cells generate signals for cancer progression, therapy resistance, and inflammatory responses. Although endogenous RNAs acting as damage-associated molecular patterns (DAMPs) for pattern recognition receptors (PRRs) may represent one such signal, these RNAs must remain unrecognized under non-pathological conditions. We show that triggering of stromal NOTCH-MYC by breast cancer cells results in a POL3-driven increase in RN7SL1, an endogenous RNA normally shielded by RNA binding proteins SRP9/14. This increase in RN7SL1 alters its stoichiometry with SRP9/14 and generates unshielded RN7SL1 in stromal exosomes. After exosome transfer to immune cells, unshielded RN7SL1 drives an inflammatory response. Upon transfer to breast cancer cells, unshielded RN7SL1 activates the PRR RIG-I to enhance tumor growth, metastasis, and therapy resistance. Corroborated by evidence from patient tumors and blood, these results demonstrate that regulation of RNA unshielding couples stromal activation with deployment of RNA DAMPs that promote aggressive features of cancer. VIDEO ABSTRACT.


Assuntos
Neoplasias da Mama/patologia , Exossomos/patologia , RNA não Traduzido/metabolismo , Células Estromais/patologia , Microambiente Tumoral , Neoplasias da Mama/metabolismo , Proteína DEAD-box 58/metabolismo , Exossomos/metabolismo , Humanos , Fatores Reguladores de Interferon/metabolismo , Células MCF-7 , Metástase Neoplásica , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Partícula de Reconhecimento de Sinal/metabolismo , Células Estromais/metabolismo , Viroses/metabolismo
14.
Mol Cell ; 67(2): 252-265.e6, 2017 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-28689661

RESUMO

While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl coenzyme A (acetyl-CoA), we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ataxia telangiectasia mutated (ATM) and AKT following DNA damage. ACLY facilitates histone acetylation at double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instability and cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Acetilcoenzima A/metabolismo , Proteína BRCA1/metabolismo , Núcleo Celular/enzimologia , Quebras de DNA de Cadeia Dupla , Reparo de DNA por Recombinação , Células A549 , ATP Citrato (pro-S)-Liase/genética , Acetilação , Animais , Proteína BRCA1/genética , Núcleo Celular/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Instabilidade Genômica , Glucose/metabolismo , Células HCT116 , Células HeLa , Histonas/metabolismo , Humanos , Melanoma Experimental/enzimologia , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Fosforilação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ligação Proteica , Processamento de Proteína Pós-Traducional , Interferência de RNA , Reparo de DNA por Recombinação/efeitos dos fármacos , Pontos de Checagem da Fase S do Ciclo Celular , Serina , Fatores de Tempo , Transfecção , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
15.
Semin Radiat Oncol ; 27(3): 289-298, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28577836

RESUMO

Immune escape of malignant cells is an important hallmark of cancer, necessary for tumor formation and progression. Accordingly, in recent years, therapies that enhance the immune system have had remarkable success in treating a myriad of malignancies. Particularly successful has been immune checkpoint blockade (ICB), which is a therapy that targets T-cell inhibitory receptors, or immune checkpoints. Despite these encouraging clinical results, most patients do not respond to such agents. Therefore, determining methods to better target and enhance the therapeutic efficacy of ICB is of paramount importance. One appealing approach is to use standard anticancer therapies, such as radiation, chemotherapy, and targeted biologics, to favorably modulate the immune system and enhance the anticancer immune response. For example, although radiation therapy has classically been thought of as a local therapy, there is significant potential for combining radiation therapy with ICB to both optimize local control and to treat metastatic disease. This concept is supported by numerous preclinical studies and clinical case reports and has since led to many early and ongoing clinical trials. However, it is still unclear how to optimally combine radiation and ICB to maximize the therapeutic effect. In this review, we highlight relevant preclinical and clinical studies in the field of radiation and ICB and discuss optimal strategies for combination therapies moving forward.


Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Terapia Combinada/métodos , Humanos , Metástase Neoplásica , Evasão Tumoral
16.
Cell ; 167(6): 1540-1554.e12, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27912061

RESUMO

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


Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Melanoma/imunologia , Melanoma/terapia , Radioimunoterapia , Animais , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Xenoenxertos , Humanos , Interferons/imunologia , Melanoma/tratamento farmacológico , Melanoma/radioterapia , Camundongos , Transplante de Neoplasias , Fator de Transcrição STAT1 , Linfócitos T/imunologia
17.
Proc Natl Acad Sci U S A ; 113(37): E5528-37, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27573852

RESUMO

Cancer is a disease driven by evolutionary selection on somatic genetic and epigenetic alterations. Here, we propose Canopy, a method for inferring the evolutionary phylogeny of a tumor using both somatic copy number alterations and single-nucleotide alterations from one or more samples derived from a single patient. Canopy is applied to bulk sequencing datasets of both longitudinal and spatial experimental designs and to a transplantable metastasis model derived from human cancer cell line MDA-MB-231. Canopy successfully identifies cell populations and infers phylogenies that are in concordance with existing knowledge and ground truth. Through simulations, we explore the effects of key parameters on deconvolution accuracy and compare against existing methods. Canopy is an open-source R package available at https://cran.r-project.org/web/packages/Canopy/.


Assuntos
Evolução Clonal/genética , Evolução Molecular , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA/genética , Exoma/genética , Heterogeneidade Genética , Humanos , Internet , Mutação , Neoplasias/patologia , Filogenia , Polimorfismo de Nucleotídeo Único , Software
18.
Cell ; 165(2): 272-5, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27058661

RESUMO

Improving efficacy of immune checkpoint blockade for cancer can be facilitated by combining these agents with each other and/or with other conventional or targeted therapies. Interferon and innate immune signaling pathways in immune and tumor cells have emerged as intriguing determinants of response and resistance, often in complex and seemingly paradoxical ways.


Assuntos
Interferons/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Transdução de Sinais , Animais , Humanos , Tolerância Imunológica , Imunidade Inata , Linfócitos/imunologia , Neoplasias/metabolismo
19.
Breast Cancer Res Treat ; 156(2): 405-6, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26993130

RESUMO

Erratum to: Breast Cancer Res Treat (2013),138:369­381,DOI 10.1007/s10549-012-2389-6. In the original publication of the article, the Fig. 4c and d were published erroneously. The revised Fig. 4 is given in this erratum.

20.
Cancer Cell ; 28(6): 685-687, 2015 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-26678335

RESUMO

The immunogenic effects of chemotherapy rely on effective activation of dendritic cells to present antigen to tumor-specific T cells. However, the signals that govern how dendritic cells seek out dying cancer cells to initiate this process are poorly understood. A recent study by Vacchelli et al. provides important insight.


Assuntos
Antraciclinas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptores de Formil Peptídeo/fisiologia , Animais , Feminino , Humanos
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