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1.
Nat Genet ; 54(7): 996-1012, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35817971

RESUMO

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.


Assuntos
DNA Polimerase II/genética , Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose/genética , Animais , DNA Polimerase III/genética , Humanos , Imunoterapia , Camundongos , Mutação , Neoplasias/genética
2.
Cancer Discov ; 12(10): 2308-2329, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-35758895

RESUMO

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. SIGNIFICANCE: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Camundongos , Antagonistas do Receptor A2 de Adenosina , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/patologia , Inflamação , Interleucina-6 , Neoplasias Renais/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Microambiente Tumoral/genética , Humanos
3.
Nat Biotechnol ; 40(4): 499-506, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34725502

RESUMO

Only a fraction of patients with cancer respond to immune checkpoint blockade (ICB) treatment, but current decision-making procedures have limited accuracy. In this study, we developed a machine learning model to predict ICB response by integrating genomic, molecular, demographic and clinical data from a comprehensively curated cohort (MSK-IMPACT) with 1,479 patients treated with ICB across 16 different cancer types. In a retrospective analysis, the model achieved high sensitivity and specificity in predicting clinical response to immunotherapy and predicted both overall survival and progression-free survival in the test data across different cancer types. Our model significantly outperformed predictions based on tumor mutational burden, which was recently approved by the U.S. Food and Drug Administration for this purpose1. Additionally, the model provides quantitative assessments of the model features that are most salient for the predictions. We anticipate that this approach will substantially improve clinical decision-making in immunotherapy and inform future interventions.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Biomarcadores Tumorais/genética , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Estudos Retrospectivos
4.
Cell ; 184(15): 4032-4047.e31, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34171309

RESUMO

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.


Assuntos
Neoplasias/genética , Neoplasias/imunologia , Splicing de RNA/genética , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Epitopos/imunologia , Etilenodiaminas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Inflamação/patologia , Camundongos Endogâmicos C57BL , Peptídeos/metabolismo , Isoformas de Proteínas/metabolismo , Pirróis/farmacologia , Splicing de RNA/efeitos dos fármacos , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
5.
Mol Cancer Res ; 19(6): 1076-1084, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33674442

RESUMO

Immune checkpoint blockade (ICB) has improved cancer care, but ICB is only effective in some patients. The molecular mechanisms that influence ICB therapy response are not completely understood. The non-classical MHC class I molecule HLA-E and its mouse ortholog, Qa-1b, present a limited set of peptides in a TAP1-dependent manner to the NKG2A/CD94 heterodimer to transduce an inhibitory signal to natural killer (NK) and CD8+ T cells. However, deficiency of TAP1 allows Qa-1b to present an alternative peptidome to Qa-1b-restricted T-cell receptors of cytotoxic T cells. In this study, we used CRISPR-Cas9 to study the relationship between TAP1, Qa-1b, and response to anti-PD1 therapy. We hypothesized that immunotherapy response in TAP1-deficient tumors would be influenced by Qa-1b. Strikingly, using a syngeneic orthotopic mouse model, we found that although TAP1-deficient tumors were resistant to anti-PD1 treatment, anti-PD1 response was significantly enhanced in tumors lacking both TAP1 and Qa-1b. This increased sensitivity is partially dependent on NK cells. TAP1-deficient tumors were associated with an increase of intratumoral regulatory T cells (Treg) and neutrophils, whereas tumors lacking both TAP1 and Qa-1b exhibited an increased CD8+ T-cell to Treg ratio. These data suggest that direct inhibition of Qa-1b may alter the immune microenvironment to reverse resistance to anti-PD1 therapy, particularly in the context of antigen-processing defects. IMPLICATIONS: This study reveals important functional crosstalk between classical TAP-dependent MHC complexes and Qa-1b/HLA-E, particularly in tumors with impaired antigen-processing machinery. This can dramatically influence immunotherapy efficacy.


Assuntos
Apresentação de Antígeno/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/terapia , Microambiente Tumoral/efeitos dos fármacos , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/imunologia , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Linhagem Celular Tumoral , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Inativação de Genes , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Depleção Linfocítica/métodos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Carga Tumoral/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
6.
Genome Med ; 11(1): 43, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340855

RESUMO

Immune checkpoint blockade therapy can elicit robust and durable responses in a variety of cancer types. While many patients do not respond, recent reports highlight a distinct group of patients whose tumors undergo rapid growth, leading to progressive disease and poor outcome. In this perspective, we synthesize and summarize some important issues surrounding hyperprogression, defining characteristics, prognostic implications, and controversies.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos Imunológicos/farmacologia , Progressão da Doença , Humanos , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Terapia de Alvo Molecular , Neoplasias/etiologia , Fatores de Risco , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do Tratamento
7.
Science ; 364(6439): 485-491, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31048490

RESUMO

Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment. We present experimental and clinical evidence showing that the degree of microsatellite instability (MSI) and resultant mutational load, in part, underlies the variable response to PD-1 blockade immunotherapy in MMR-d human and mouse tumors. The extent of response is particularly associated with the accumulation of insertion-deletion (indel) mutational load. This study provides a rationale for the genome-wide characterization of MSI intensity and mutational load to better profile responses to anti-PD-1 immunotherapy across MMR-deficient human cancers.


Assuntos
Reparo de Erro de Pareamento de DNA/genética , Imunoterapia/métodos , Instabilidade de Microssatélites , Neoplasias/genética , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos/uso terapêutico , Variação Genética , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos , Proteína 2 Homóloga a MutS/genética , Mutação , Resultado do Tratamento
8.
Mol Microbiol ; 110(4): 596-615, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30192418

RESUMO

ExoS/ChvI two-component signaling in the nitrogen-fixing α-proteobacterium Sinorhizobium meliloti is required for symbiosis and regulates exopolysaccharide production, motility, cell envelope integrity and nutrient utilization in free-living bacteria. However, identification of many ExoS/ChvI direct transcriptional target genes has remained elusive. Here, we performed chromatin immunoprecipitation followed by microarray analysis (chIP-chip) to globally identify DNA regions bound by ChvI protein in S. meliloti. We then performed qRT-PCR with chvI mutant strains to test ChvI-dependent expression of genes downstream of the ChvI-bound DNA regions. We identified 64 direct target genes of ChvI, including exoY, rem and chvI itself. We also identified ChvI direct target candidates, like exoR, that are likely controlled by additional regulators. Analysis of upstream sequences from the 64 ChvI direct target genes identified a 15 bp-long consensus sequence. Using electrophoretic mobility shift assays and transcriptional fusions with exoY, SMb21440, SMc00084, SMc01580, chvI, and ropB1, we demonstrated this consensus sequence is important for ChvI binding to DNA and transcription of ChvI direct target genes. Thus, we have comprehensively identified ChvI regulon genes and a 'ChvI box' bound by ChvI. Many ChvI direct target genes may influence the cell envelope, consistent with the critical role of ExoS/ChvI in growth and microbe-host interactions.


Assuntos
Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica/genética , Sinorhizobium meliloti/genética , Sinorhizobium meliloti/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/genética , Sítios de Ligação/genética , Proteínas de Ligação a DNA/genética , Genoma Bacteriano/genética , Glucosiltransferases/genética , Ligação Proteica/genética , Transdução de Sinais , Simbiose/genética , Fatores de Transcrição/genética , Transcrição Gênica/genética
9.
Cell Rep ; 20(7): 1623-1640, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28813674

RESUMO

At the root of most fatal malignancies are aberrantly activated transcriptional networks that drive metastatic dissemination. Although individual metastasis-associated genes have been described, the complex regulatory networks presiding over the initiation and maintenance of metastatic tumors are still poorly understood. There is untapped value in identifying therapeutic targets that broadly govern coordinated transcriptional modules dictating metastatic progression. Here, we reverse engineered and interrogated a breast cancer-specific transcriptional interaction network (interactome) to define transcriptional control structures causally responsible for regulating genetic programs underlying breast cancer metastasis in individual patients. Our analyses confirmed established pro-metastatic transcription factors, and they uncovered TRIM25 as a key regulator of metastasis-related transcriptional programs. Further, in vivo analyses established TRIM25 as a potent regulator of metastatic disease and poor survival outcome. Our findings suggest that identifying and targeting keystone proteins, like TRIM25, can effectively collapse transcriptional hierarchies necessary for metastasis formation, thus representing an innovative cancer intervention strategy.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Redes Reguladoras de Genes , Genes Reporter , Xenoenxertos , Humanos , Luciferases/genética , Luciferases/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transdução de Sinais , Análise de Sobrevida , Biologia de Sistemas , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
10.
Elife ; 2: e00822, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24137534

RESUMO

mir-17-92, a potent polycistronic oncomir, encodes six mature miRNAs with complex modes of interactions. In the Eµ-myc Burkitt's lymphoma model, mir-17-92 exhibits potent oncogenic activity by repressing c-Myc-induced apoptosis, primarily through its miR-19 components. Surprisingly, mir-17-92 also encodes the miR-92 component that negatively regulates its oncogenic cooperation with c-Myc. This miR-92 effect is, at least in part, mediated by its direct repression of Fbw7, which promotes the proteosomal degradation of c-Myc. Thus, overexpressing miR-92 leads to aberrant c-Myc increase, imposing a strong coupling between excessive proliferation and p53-dependent apoptosis. Interestingly, miR-92 antagonizes the oncogenic miR-19 miRNAs; and such functional interaction coordinates proliferation and apoptosis during c-Myc-induced oncogenesis. This miR-19:miR-92 antagonism is disrupted in B-lymphoma cells that favor a greater increase of miR-19 over miR-92. Altogether, we suggest a new paradigm whereby the unique gene structure of a polycistronic oncomir confers an intricate balance between oncogene and tumor suppressor crosstalk. DOI:http://dx.doi.org/10.7554/eLife.00822.001.


Assuntos
Apoptose/fisiologia , MicroRNAs/fisiologia , Oncogenes , Animais , Apoptose/genética , Células Cultivadas , Camundongos
11.
J Bacteriol ; 191(22): 6833-42, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19749054

RESUMO

The Sinorhizobium meliloti ExoS/ChvI two-component signaling pathway is required for the development of a nitrogen-fixing symbiosis between S. meliloti and its plant hosts. ExoS/ChvI also has important roles in regulating succinoglycan production, biofilm formation, motility, nutrient utilization, and the viability of free-living bacteria. Previous microarray experiments with an exoS96::Tn5 mutant indicated that ExoS/ChvI influences the expression of a few hundred genes, complicating the investigation of which downstream genes respond directly or indirectly to ExoS/ChvI regulation. To focus our study of ExoS/ChvI transcriptional target genes, we performed transcriptional profiling with chvI gain-of-function and reduced-function strains. The chvI gain-of-function strain that we used contains a dominant gain-of-function chvI allele in addition to wild-type chvI. We identified genes that, relative to their expression level in the wild type, are both upregulated in the chvI gain-of-function strain and downregulated in the reduced-function strain or vice versa. Guided by this focused set of genes, we performed gel mobility shift assays and demonstrated that ChvI directly binds the intergenic regions upstream of ropB1, SMb21440, and SMc01580. Furthermore, DNase I footprint analysis of the region upstream of SMc01580 identified a specific DNA sequence bound by ChvI and allowed the discovery of a possible motif for ChvI binding. Our results provide insight into the mechanism of how ExoS/ChvI regulates its downstream targets and lay a foundation for studying this conserved pathway with critical roles in free-living and symbiotic bacteria.


Assuntos
Proteínas de Bactérias/fisiologia , Regulação Bacteriana da Expressão Gênica/fisiologia , Sinorhizobium meliloti/metabolismo , Fatores de Transcrição/fisiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sequência de Bases , DNA/metabolismo , Pegada de DNA , Ensaio de Desvio de Mobilidade Eletroforética , Regulação Bacteriana da Expressão Gênica/genética , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica , Sinorhizobium meliloti/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
Mol Microbiol ; 69(5): 1290-303, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18631237

RESUMO

Sinorhizobium meliloti requires ExoS/ChvI two-component signalling to establish a nitrogen-fixing symbiosis with legume hosts. The importance of ExoS/ChvI signalling in microbe-host interactions is underscored by the requirement of ExoS/ChvI orthologues for virulence of the related alpha-proteobacteria Agrobacterium tumefaciens and Brucella abortus. In S. meliloti, ExoS/ChvI is a key regulator of gene expression for exopolysaccharide synthesis, biofilm formation, motility, nutrient utilization and free-living viability. Previously, we showed that the novel conserved regulator ExoR interacts genetically with both ExoS and ChvI, and localizes to the periplasm of S. meliloti. Here, we show that ExoR physically associates with ExoS and that this association is important for regulating ExoS/ChvI signalling. We have identified point mutations in the Sel1-like repeat region of ExoR that disrupt binding to ExoS and cause a dramatic increase in ExoS/ChvI-dependent gene expression. Furthermore, we have found that physical interaction with ExoS stabilizes the ExoR protein. Together, our results indicate that ExoR binds to ExoS in the periplasm of S. meliloti to inhibit ExoS/ChvI activity, and that ExoR represents a novel periplasmic inhibitor of two-component signalling.


Assuntos
Proteínas de Bactérias/metabolismo , Regulação para Baixo , Regulação Bacteriana da Expressão Gênica , Periplasma/metabolismo , Polissacarídeos Bacterianos/metabolismo , Transdução de Sinais , Sinorhizobium meliloti/fisiologia , Proteínas de Bactérias/genética , Mutação , Periplasma/genética , Polissacarídeos Bacterianos/genética , Ligação Proteica , Sinorhizobium meliloti/genética , Sinorhizobium meliloti/crescimento & desenvolvimento , Simbiose
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