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1.
Int J Radiat Oncol Biol Phys ; 114(4): 666-675, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-35643252

RESUMO

PURPOSE: We retrospectively evaluated outcomes after radiation therapy for patients with oligoprogression on immune checkpoint inhibitors (ICI). METHODS AND MATERIALS: We identified patients irradiated to ≤5 progressive lesions while receiving ICI between 2010 and 2020. We excluded patients whose systemic therapy was switched after radiation but before progression. We evaluated predictors of local control (LC), progression-free survival (PFS) and overall survival (OS). RESULTS: We screened 1423 patients and identified 120 who were eligible; the most common histologies were lung cancer (n = 59) and melanoma (n = 36). The median number of oligoprogressive lesions was 1. For the median LC of irradiated oligoprogressive lesions, PFS and OS were not reached at 6.41 (4.67-7.66) and 29.80 (22.54-43.33) months, respectively. Tumor histology, radiated site, or radiation modality were not associated with LC, PFS, or OS. Local response to radiation (P < .0001) and radiation of newly developed lesions (P = .02) were associated with LC. Predictors of PFS on univariate and multivariate analyses were best response to radiation (P = .006) and high programmed death ligand 1 tumor proportion score (P = .02). On multivariate analyses, OS was associated with cumulative oligoprogressive lesion volumes (P = .02) and duration of ICI before oligoprogression (P = .03). CONCLUSIONS: Promising outcomes were observed among patients irradiated for oligoprogression on ICI, especially those with a favorable local response, high tumor programmed death ligand 1 expression, and those receiving ICI for longer periods before oligoprogression. These data can help identify patients well suited for radiation therapy versus those who should switch systemic treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Estudos Retrospectivos
2.
Nat Commun ; 12(1): 6218, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34711820

RESUMO

Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cell death in vivo are currently unclear. Using a mouse model of BCR-ABL+ B-cell acute lymphoblastic leukemia, we show that chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of the cytokine IL-6. The chemotherapeutic doxorubicin is curative in IL-6-deficient mice through the induction of CD8+ T-cell-mediated anti-cancer responses, while moderately extending lifespan in wild type tumor-bearing mice. We also show that IL-6 suppresses the effectiveness of immune-checkpoint inhibition with anti-PD-L1 blockade. Our results suggest that IL-6 is a key regulator of anti-cancer immune responses induced by genotoxic stress and that its inhibition can switch cancer cell clearance from primarily apoptotic to immunogenic, promoting and maintaining durable anti-tumor immune responses.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Interleucina-6/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Microambiente Tumoral , Animais , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia
3.
J Natl Compr Canc Netw ; 19(5): 567-576, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34030132

RESUMO

Treatment options in locally advanced hepatocellular carcinoma (HCC) have evolved considerably over the past few years with the recent approval of multiple systemic therapies and significant advances in locoregional therapy. Given the poor prognosis for patients with unresectable HCC, there is significant interest in rationally designed combination therapies. This article reviews the treatment options available to patients with locally advanced HCC and discusses the rationale, ongoing trials, and future prospects for combining locoregional and systemic therapy in both the definitive and neoadjuvant settings.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Terapia Combinada , Humanos , Neoplasias Hepáticas/tratamento farmacológico
4.
Genes Dev ; 30(16): 1811-21, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27566778

RESUMO

Cancer therapy targets malignant cells that are surrounded by a diverse complement of nonmalignant stromal cells. Therapy-induced damage of normal cells can alter the tumor microenvironment, causing cellular senescence and activating cancer-promoting inflammation. However, how these damage responses are regulated (both induced and resolved) to preserve tissue homeostasis and prevent chronic inflammation is poorly understood. Here, we detail an acute chemotherapy-induced secretory response that is self-limiting in vitro and in vivo despite the induction of cellular senescence. We used tissue-specific knockout mice to demonstrate that endothelial production of the proinflammatory cytokine IL-6 promotes chemoresistance and show that the chemotherapeutic doxorubicin induces acute IL-6 release through reactive oxygen species-mediated p38 activation in vitro. Doxorubicin causes endothelial senescence but, surprisingly, without a typical senescence secretory response. We found that endothelial cells repress senescence-associated inflammation through the down-regulation of PI3K/AKT/mTOR signaling and that reactivation of this pathway restores senescence-associated inflammation. Thus, we describe a mechanism by which damage-associated paracrine secretory responses are restrained to preserve tissue homeostasis and prevent chronic inflammation.


Assuntos
Senescência Celular/fisiologia , Células Endoteliais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/fisiologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Células Endoteliais/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/genética , Microambiente Tumoral/efeitos dos fármacos
5.
Cell ; 156(3): 590-602, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-24485462

RESUMO

Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment refractory B cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF, and TNFα from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemoimmunotherapeutic regimen represents a potent strategy for using conventional anticancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.


Assuntos
Modelos Animais de Doenças , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Microambiente Tumoral , Animais , Ciclofosfamida/uso terapêutico , Citocinas/imunologia , Resistencia a Medicamentos Antineoplásicos , Xenoenxertos , Humanos , Imunidade Inata , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Macrófagos/imunologia , Camundongos , Transplante de Neoplasias
6.
Biochim Biophys Acta ; 1808(1): 382-93, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20920465

RESUMO

Cell penetrating peptides (CPPs) are peptides displaying the ability to cross cell membranes and transport cargo molecules inside cells. Several uptake mechanisms (endocytic or direct translocation through the membrane) are being considered, but the interaction between the CPP and the cell membrane is certainly a preliminary key point to the entry of the peptide into the cell. In this study, we used three basic peptides: RL9 (RRLLRRLRR-NH(2)), RW9 (RRWWRRWRR-NH(2)) and R9 (RRRRRRRRR-NH(2)). While RW9 and R9 were internalised into wild type Chinese Hamster Ovary cells (CHO) and glycosaminoglycan-deficient CHO cells, at 4°C and 37°C, RL9 was not internalised into CHO cells. To better understand the differences between RW9, R9 and RL9 in terms of uptake, we studied the interaction of these peptides with model lipid membranes. The effect of the three peptides on the thermotropic phase behaviour of a zwitterionic lipid (DMPC) and an anionic lipid (DMPG) was investigated with differential scanning calorimetry (DSC). The presence of negative charges on the lipid headgroups appeared to be essential to trigger the peptide/lipid interaction. RW9 and R9 disturbed the main phase transition of DMPG, whereas RL9 did not induce significant effects. Isothermal titration calorimetry (ITC) allowed us to study the binding of these peptides to large unilamellar vesicles (LUVs). RW9 and R9 proved to have about ten fold more affinity for DSPG LUVs than RL9. With circular dichroism (CD) and NMR spectroscopy, the secondary structure of RL9, RW9 and R9 in aqueous buffer or lipid/detergent conditions was investigated. Additionally, we tested the antimicrobial activity of these peptides against Escherichia coli and Staphylococcus aureus, as CPPs and antimicrobial peptides are known to share several common characteristics. Only RW9 was found to be mildly bacteriostatic against E. coli. These studies helped us to get a better understanding as to why R9 and RW9 are able to cross the cell membrane while RL9 remains bound to the surface without entering the cell.


Assuntos
Arginina/química , Membrana Celular/metabolismo , Peptídeos/química , Sequência de Aminoácidos , Animais , Antibacterianos/farmacologia , Células CHO , Varredura Diferencial de Calorimetria/métodos , Dicroísmo Circular , Cricetinae , Cricetulus , Escherichia coli/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Staphylococcus aureus/metabolismo
7.
Environ Microbiol ; 12(8): 2190-203, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21966913

RESUMO

In horizontally transmitted mutualisms between marine animals and their bacterial partners, the host environment promotes the initial colonization by specific symbionts that it harvests from the surrounding bacterioplankton. Subsequently, the host must develop long-term tolerance to immunogenic bacterial molecules, such as peptidoglycan and lipopolysaccaride derivatives. We describe the characterization of the activity of a host peptidoglycan recognition protein (EsPGRP2) during establishment of the symbiosis between the squid Euprymna scolopes and its luminous bacterial symbiont Vibrio fischeri. Using confocal immunocytochemistry, we localized EsPGRP2 to all epithelial surfaces of the animal, and determined that it is exported in association with mucus shedding. Most notably, EsPGRP2 was released by the crypt epithelia into the extracellular spaces housing the symbionts. This translocation occurred only after the symbionts had triggered host morphogenesis, a process that is induced by exposure to the peptidoglycan monomer tracheal cytotoxin (TCT), a bacterial 'toxin' that is constitutively exported by V. fischeri. Enzymatic analyses demonstrated that, like many described PGRPs, EsPGRP2 has a TCT-degrading amidase activity. The timing of EsPGRP2 export into the crypts provides evidence that the host does not export this protein until after TCT induces morphogenesis, and thereafter EsPGRP2 is constantly present in the crypts ameliorating the effects of V. fischeri TCT.


Assuntos
Aliivibrio fischeri/crescimento & desenvolvimento , Toxinas Bacterianas/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Decapodiformes/metabolismo , Decapodiformes/microbiologia , Simbiose , Amidoidrolases/metabolismo , Animais , Citotoxinas/antagonistas & inibidores , Epitélio/metabolismo , Morfogênese , Muco/química
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