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1.
Nat Genet ; 53(3): 332-341, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33649592

RESUMO

Resistance to immune checkpoint inhibitors (ICIs) is a key challenge in cancer therapy. To elucidate underlying mechanisms, we developed Perturb-CITE-sequencing (Perturb-CITE-seq), enabling pooled clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 perturbations with single-cell transcriptome and protein readouts. In patient-derived melanoma cells and autologous tumor-infiltrating lymphocyte (TIL) co-cultures, we profiled transcriptomes and 20 proteins in ~218,000 cells under ~750 perturbations associated with cancer cell-intrinsic ICI resistance (ICR). We recover known mechanisms of resistance, including defects in the interferon-γ (IFN-γ)-JAK/STAT and antigen-presentation pathways in RNA, protein and perturbation space, and new ones, including loss/downregulation of CD58. Loss of CD58 conferred immune evasion in multiple co-culture models and was downregulated in tumors of melanoma patients with ICR. CD58 protein expression was not induced by IFN-γ signaling, and CD58 loss conferred immune evasion without compromising major histocompatibility complex (MHC) expression, suggesting that it acts orthogonally to known mechanisms of ICR. This work provides a framework for the deciphering of complex mechanisms by large-scale perturbation screens with multimodal, single-cell readouts, and discovers potentially clinically relevant mechanisms of immune evasion.


Assuntos
Antígenos CD58/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Melanoma/patologia , Análise de Célula Única/métodos , Evasão Tumoral , Antígenos CD58/genética , Antígenos CD58/metabolismo , Sistemas CRISPR-Cas , Técnicas de Cocultura , Biologia Computacional/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Epitopos/genética , Técnicas de Inativação de Genes , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/patologia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Análise de Sequência de RNA , Evasão Tumoral/genética
2.
Nat Commun ; 12(1): 729, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526794

RESUMO

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.


Assuntos
/uso terapêutico , Linfócitos/imunologia , Neoplasias/tratamento farmacológico , Neutrófilos/imunologia , Idoso , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Seguimentos , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Retrospectivos
3.
Nat Commun ; 12(1): 1237, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623012

RESUMO

Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression.


Assuntos
Anticorpos Biespecíficos/imunologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/imunologia , Janus Quinase 2/metabolismo , Neoplasias/imunologia , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular , Citotoxicidade Imunológica , Humanos , Interferon gama/metabolismo , Camundongos , Transdução de Sinais , Transcriptoma/genética
4.
Nat Rev Cancer ; 21(2): 89-103, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432169

RESUMO

Aneuploidy has been recognized as a hallmark of tumorigenesis for more than 100 years, but the connection between chromosomal errors and malignant growth has remained obscure. New evidence emerging from both basic and clinical research has illuminated a complicated relationship: despite its frequency in human tumours, aneuploidy is not a universal driver of cancer development and instead can exert substantial tumour-suppressive effects. The specific consequences of aneuploidy are highly context dependent and are influenced by a cell's genetic and environmental milieu. In this Review, we discuss the diverse facets of cancer biology that are shaped by aneuploidy, including metastasis, drug resistance and immune recognition, and we highlight aneuploidy's distinct roles as both a tumour promoter and an anticancer vulnerability.


Assuntos
Aneuploidia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Evasão Tumoral/imunologia , Animais , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Camundongos , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Fenótipo , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
5.
Nat Commun ; 11(1): 6410, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335088

RESUMO

Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.


Assuntos
Sarcoma/terapia , Análise de Célula Única/métodos , Microambiente Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Transplante de Medula Óssea , Linfócitos T CD8-Positivos/imunologia , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Camundongos Endogâmicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sarcoma/genética , Sarcoma/imunologia , Evasão Tumoral , Microambiente Tumoral/genética , Sequenciamento Completo do Exoma
6.
Lancet Oncol ; 21(9): e419-e430, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888471

RESUMO

Notable advances have been achieved in the treatment of cancer since the advent of immunotherapy, and immune checkpoint inhibitors have shown clinical benefit across a wide variety of tumour types. Nevertheless, most patients still progress on these treatments, highlighting the importance of unravelling the underlying mechanisms of primary resistance to immunotherapy. A well described biomarker of non-responsiveness to immune checkpoint inhibitors is the absence or low presence of lymphocytes in the tumour microenvironment, so-called cold tumours. There are five mechanisms of action that have the potential to turn cold tumours into so-called hot and inflamed tumours, hence increasing the tumour's responsiveness to immunotherapy-increasing local inflammation, neutralising immunosuppression at the tumour site, modifying the tumour vasculature, targeting the tumour cells themselves, or increasing the frequency of tumour-specific T cells. In this Review, we discuss preclinical data that serves as the basis for ongoing immunotherapy clinical trials for the treatment of non-immunoreactive tumours, as well as reviewing clinical and translational data where available. We explain how improving our understanding of the underlying mechanisms of primary resistance to immunotherapy will help elucidate an increasingly granular view of the tumour microenvironment cellular composition, functional status, and cellular localisation, with the goal of further therapy refinement.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Imunoterapia/efeitos adversos , Inflamação/terapia , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunidade Celular/imunologia , Inflamação/imunologia , Inflamação/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Microambiente Tumoral/imunologia
7.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
8.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917858

RESUMO

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
9.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188384, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531324

RESUMO

Cancer regression often fails after systemic immune activation, especially for solid tumors due to their local immunosuppressive microenvironments. Among these, the pancreatic cancer microenvironment is unique and an important reason for resistance to anti-cancer treatments that include immunotherapy. In this review, the three main "BAD" characteristics that create and maintain this immunosuppressive microenvironment are discussed for effector T cells: Barriers to overcome, Attraction problems, and their Disabilities. These inhibit both effector T-cell activation and infiltration, reducing immunotherapy effectiveness. Combination approaches for killing the "BAD" aim to normalize the tumor microenvironment and are recommended to enhance anti-cancer immune-system efficacy in pancreatic cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/efeitos dos fármacos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
10.
Cancer Res ; 80(12): 2441-2450, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32245794

RESUMO

The DNA methyltransferase inhibitors (DNMTi) 5-azacytidine and 5-aza-2-deoxycytidine have been approved for the treatment of different types of hematologic malignancies. However, only about 50% of patients respond to treatment. Therefore, a more comprehensive understanding of the molecular changes in patients treated with DNMTi is needed. Here, we examined gene expression profiles in a total of 150 RNA samples from two adult cohorts and one pediatric cohort with hematologic cancers taken before, during, and after treatment with 5-azacytidine (40 patients; 15 nonresponders, 25 responders). Using each patient as their own control, malignant cells showed preferential activation of a subset of evolutionarily young transposable elements (TE), including endogenous retroviral long terminal repeats (LTR), short and long interspersed nuclear elements (SINE and LINE), and the type I IFN pathway in responders, all independent of disease classification. Transfection of eight upregulated LTRs into recipient human cells in culture showed robust and heterogenous activation of six genes in the type I IFN pathway. These results, obtained in diverse hematologic disease entities, show that common targets (TE) activated by the same drug (5-azacytidine) elicit an immune response, which may be important for patient's responses to DNMTi. SIGNIFICANCE: Activation of specific classes of evolutionarily young transposable elements can lead to activation of the innate immune system.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Elementos de DNA Transponíveis/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Imunidade Inata/genética , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Estudos de Coortes , Elementos de DNA Transponíveis/genética , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Retrovirus Endógenos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Mimetismo Molecular/imunologia , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Regulação para Cima/efeitos dos fármacos
11.
Nat Med ; 26(5): 732-740, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341578

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR-Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.


Assuntos
Sistemas CRISPR-Cas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Edição de Genes/métodos , Imunoterapia Adotiva , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/genética , Linfócitos T/transplante , Adolescente , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Estudos de Viabilidade , Feminino , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo , Resultado do Tratamento , Adulto Jovem
12.
Cell ; 180(5): 895-914.e27, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142680

RESUMO

A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias/tratamento farmacológico , Proclorperazina/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Apresentação do Antígeno/efeitos dos fármacos , Biópsia , Cetuximab/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Endocitose/efeitos dos fármacos , Endocitose/imunologia , Xenoenxertos , Humanos , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células MCF-7 , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Trastuzumab/farmacologia
13.
Cancer Res ; 80(10): 1942-1956, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32127354

RESUMO

The recent success of checkpoint blockade therapies has established immunotherapy as one of the most promising treatments for melanoma. Nonetheless, a complete curative response following immunotherapy is observed only in a fraction of patients. To identify what factors limit the efficacy of immunotherapies, we established mouse models that cease to respond to immunotherapies once their tumors exceed a certain stage. Analysis of the immune systems of the organisms revealed that the numbers of tumor-infiltrating dendritic cells (TIDC) drastically decreased with time. Further, in contrast to the current paradigm, once melanoma was established, TIDC did not migrate into sentinel lymph nodes. Instead, they underwent local cell death due to excessive phagocytosis of lysosomes. Importantly, TIDC were required to license the cytotoxic activity of tumor CD8+ T cells, and in their absence, T cells did not lyse melanoma cells. Our results offer a paradigm shift regarding the role of TIDC and a framework to increase the efficacy of immunotherapies. SIGNIFICANCE: This work redefines the role of monocyte-derived dendritic cells in melanoma and provides a novel strategy to increase the efficacy of T-cell-based immunotherapies in nonresponding individuals. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/1942/F1.large.jpg.


Assuntos
Células Dendríticas/patologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Lisossomos , Melanoma/imunologia , Animais , Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunoterapia , Ativação Linfocitária/imunologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL
14.
Proc Natl Acad Sci U S A ; 117(14): 8022-8031, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32213589

RESUMO

Innate immune receptors such as toll-like receptors (TLRs) provide critical molecular links between innate cells and adaptive immune responses. Here, we studied the CD40 pathway as an alternative bridge between dendritic cells (DCs) and adaptive immunity in cancer. Using an experimental design free of chemo- or radiotherapy, we found CD40 activation with agonistic antibodies (⍺CD40) produced complete tumor regressions in a therapy-resistant pancreas cancer model, but only when combined with immune checkpoint blockade (ICB). This effect, unachievable with ICB alone, was independent of TLR, STING, or IFNAR pathways. Mechanistically, αCD40/ICB primed durable T cell responses, and efficacy required DCs and host expression of CD40. Moreover, ICB drove optimal generation of polyfunctional T cells in this "cold" tumor model, instead of rescuing T cell exhaustion. Thus, immunostimulation via αCD40 is sufficient to synergize with ICB for priming. Clinically, combination αCD40/ICB may extend efficacy in patients with "cold" and checkpoint-refractory tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígenos CD40/agonistas , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
15.
Nat Commun ; 11(1): 931, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071302

RESUMO

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Glioma/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-1/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Imagem por Ressonância Magnética , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
16.
Cancer Immunol Immunother ; 69(5): 717-730, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32036449

RESUMO

Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8+ T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK- and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.


Assuntos
Envelhecimento/imunologia , Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biópsia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Seguimentos , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/imunologia , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Intervalo Livre de Progressão , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia
17.
Int Immunopharmacol ; 80: 106242, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32014811

RESUMO

The inhibitory effects of programmed cell death 1 (PD-1) receptor on tumor specific T cells were mainly investigated at tumor site. While PD-1 expression can be rapidly unregulated upon T cell activation at lymphoid tissues, little is known about where PD-1 signal exerts its inhibitory function in tumor-bearing host. To address this issue, we assessed the effects of PD-1 on vaccine induced activation of splenic CD8 + T cells in mice. The vaccine consisted of mice CD8 + T cell epitope peptide and poly IC. After vaccination, spleen or tumor tissues were dissociated, IFN-γ synthesis and PD-1 expression by CD8 + T cells were detected by flow cytometry. We found that CD8 + T cells could be successfully activated in spleen after immunization, characterized by the capability of producing IFN-γ when encountering relevant peptide. These activated splenic CD8 + T cells also expressed a high level of PD-1. Although PD-L1 expression in spleen parenchyma was also increased after vaccination, PD-1 blockade did not affect the activation of splenic CD8 + T cells, but enhanced the anti-tumor effects of peptide vaccine. This synergetic effect of peptide vaccine plus PD-1 blockade was coupled with increased aggregation of IFN-γ + CD8 + tumor infiltrated lymphocytes (TILs), rather than CD4 + TILs. The results indicated that for tumor-bearing host, PD-1 pathway exerted its inhibitory function at tumor site and PD-1 expression on the splenic CD8 + T cells correlated positively with IFN-γ synthesis.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma Experimental/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Baço/citologia , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral/transplante , Resistencia a Medicamentos Antineoplásicos/imunologia , Epitopos de Linfócito T/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Imunoterapia/métodos , Interferon gama/metabolismo , Oxirredutases Intramoleculares/administração & dosagem , Oxirredutases Intramoleculares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Poli I-C/imunologia , Organismos Livres de Patógenos Específicos , Baço/imunologia , Baço/metabolismo , Baço/patologia , Regulação para Cima/imunologia , Vacinas de Subunidades/administração & dosagem
18.
J Clin Invest ; 130(3): 1199-1216, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32015230

RESUMO

Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Apc-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell-mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Imunológicos/farmacologia , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoterapia , Neovascularização Patológica , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/imunologia , Angiopoietina-2/genética , Angiopoietina-2/imunologia , Animais , Linhagem Celular , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/imunologia , Camundongos , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/terapia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/imunologia
19.
Int Immunopharmacol ; 80: 106247, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32007710

RESUMO

Recently, immunotherapy has evolved into a true treatment modality with the approval of PD-1 and PD-L1 inhibitors as the standard care for first-line treatment in patients with non-small cell lung cancer (NSCLC). Until now, for patients with advanced NSCLC, treatment of targeting immune checkpoints reveals a promising survival benefit, and some patients even get long term survive, which creates a paradigm shift in NSCLC treatment. However, many issues or problems are also appearing in clinical practice, such as the lower overall efficacy rate (20-40%), treatment modes, populations choice of immunotherapy, drug resistance, and safety, etc. Thus, in this review, we will mainly summarize and discuss the recent development and confusion of PD-1/PD-L1 inhibitors for advanced NSCLC patients based on current clinical studies.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/tendências , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia/métodos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Mutação , Estadiamento de Neoplasias , Seleção de Pacientes , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
20.
Eur J Cancer ; 128: 27-37, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32109848

RESUMO

AIM: Tumour-associated macrophages (TAMs) are prominent immune cells infiltrating in solid tumours with phenotypic and functional heterogeneity. However, the clinical significance of heterogeneous subtypes of TAMs in gastric cancer still remains obscure. Here, we aimed to explore the clinical significance of TAMs expressing dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) and its relevance with immune contexture in gastric cancer. METHODS: We selected 453 formalin-fixed and paraffin-embedded samples and 51 fresh tissue specimens of patients with gastric cancer from Zhongshan Hospital. The association of DC-SIGN+ macrophages with clinicopathological parameters, overall survival (OS) and responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) was inspected. Immunohistochemistry (IHC) and flow cytometry (FCM) were applied to characterize immune cells in gastric cancer. RESULTS: We demonstrated that high intratumoral DC-SIGN+ macrophages infiltration predicted poor OS and inferior therapeutic responsiveness to fluorouracil-based ACT in patients with gastric cancer. Furthermore, higher infiltration of DC-SIGN+ macrophages indicated an increased number of Foxp3+ regulatory T cells (Tregs), CD8+ T cells and a higher ratio of Foxp3+/CD8+ within the tumour microenvironment (TME). In addition, CD8+ T cells in DC-SIGN+ macrophages high subgroup were functionally impaired, showing decreased interferon-γ (IFN-γ), granzyme B (GZMB) and perforin production yet elevated programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression. CONCLUSIONS: DC-SIGN+ macrophages were associated with immunoinvasive TME and indicated poor prognosis and inferior therapeutic responsiveness to fluorouracil-based ACT. DC-SIGN+ macrophages might be an independent prognosticator and a potential immunotherapeutic target for gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Moléculas de Adesão Celular/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Receptores de Superfície Celular/metabolismo , Neoplasias Gástricas/imunologia , Evasão Tumoral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Seguimentos , Gastrectomia , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Estômago/citologia , Estômago/imunologia , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Resultado do Tratamento
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