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2.
Nat Cancer ; 4(9): 1258-1272, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37537301

RESUMO

The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D-NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Animais , Humanos , Camundongos , Antígenos/metabolismo , Linfócitos T CD8-Positivos/patologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo
3.
Neurooncol Adv ; 5(1): vdad035, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37207119

RESUMO

Background: The nervous and immune systems interact in a reciprocal manner, both under physiologic and pathologic conditions. Literature spanning various CNS pathologies including brain tumors, stroke, traumatic brain injury and de-myelinating diseases describes a number of associated systemic immunologic changes, particularly in the T-cell compartment. These immunologic changes include severe T-cell lymphopenia, lymphoid organ contraction, and T-cell sequestration within the bone marrow. Methods: We performed an in-depth systematic review of the literature and discussed pathologies that involve brain insults and systemic immune derangements. Conclusions: In this review, we propose that the same immunologic changes hereafter termed 'systemic immune derangements', are present across CNS pathologies and may represent a novel, systemic mechanism of immune privilege for the CNS. We further demonstrate that systemic immune derangements are transient when associated with isolated insults such as stroke and TBI but persist in the setting of chronic CNS insults such as brain tumors. Systemic immune derangements have vast implications for informed treatment modalities and outcomes of various neurologic pathologies.

4.
Curr Neurol Neurosci Rep ; 23(6): 263-276, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37154886

RESUMO

PURPOSE OF REVIEW: The management of isocitrate dehydrogenase (IDH)-wildtype glioblastomas is an area of unmet need. Despite multimodal therapy incorporating maximal safe resection, radiotherapy, and temozolomide, clinical outcomes remain poor. At disease progression or relapse, available systemic agents such as temozolomide, lomustine, and bevacizumab have limited efficacy. We review the recent advances in the treatment of IDH-wildtype glioblastomas. RECENT FINDINGS: A broad repertoire of systemic agents is in the early stages of development, encompassing the areas of precision medicine, immunotherapy, and repurposed medications. The use of medical devices may present opportunities to bypass the blood-brain barrier. Novel clinical trial designs aim to efficiently test treatment options to advance the field. There are a number of emerging treatment options for IDH-wildtype glioblastomas which are undergoing evaluation in clinical trials. Advances in our scientific understanding of IDH-wildtype glioblastomas offer hope and the prospect of incremental improvements in clinical outcomes.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioblastoma/genética , Glioblastoma/terapia , Imunoterapia , Isocitrato Desidrogenase/genética , Mutação , Prognóstico , Temozolomida/uso terapêutico
5.
Clin Cancer Res ; 27(21): 5742-5752, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34127507

RESUMO

In chronic infections and in cancer, persistent antigen stimulation under suboptimal conditions can lead to the induction of T-cell exhaustion. Exhausted T cells are characterized by an increased expression of inhibitory markers and a progressive and hierarchical loss of function. Although cancer-induced exhaustion in CD8 T cells has been well-characterized and identified as a therapeutic target (i.e., via checkpoint inhibition), in-depth analyses of exhaustion in other immune cell types, including CD4 T cells, is wanting. While perhaps attributable to the contextual discovery of exhaustion amidst chronic viral infection, the lack of thorough inquiry into CD4 T-cell exhaustion is particularly surprising given their important role in orchestrating immune responses through T-helper and direct cytotoxic functions. Current work suggests that CD4 T-cell exhaustion may indeed be prevalent, and as CD4 T cells have been implicated in various disease pathologies, such exhaustion is likely to be clinically relevant. Defining phenotypic exhaustion in the various CD4 T-cell subsets and how it influences immune responses and disease severity will be crucial to understanding collective immune dysfunction in a variety of pathologies. In this review, we will discuss mechanistic and clinical evidence for CD4 T-cell exhaustion in cancer. Further insight into the derivation and manifestation of exhaustive processes in CD4 T cells could reveal novel therapeutic targets to abrogate CD4 T-cell exhaustion in cancer and induce a robust antitumor immune response.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Neoplasias/imunologia , Animais , Humanos , Camundongos
6.
J Neurooncol ; 151(1): 3-12, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32542437

RESUMO

INTRODUCTION: The overall survival in patients with gliomas has not significantly increased in the modern era, despite advances such as immunotherapy. This is in part due to their notorious ability to suppress local and systemic immune responses, severely restricting treatment efficacy. METHODS: We have reviewed the preclinical and clinical evidence for immunosuppression seen throughout the disease process in gliomas. This review aims to discuss the various ways that brain tumors, and gliomas in particular, co-opt the body's immune system to evade detection and ensure tumor survival and proliferation. RESULTS: A multitude of mechanisms are discussed by which neoplastic cells evade detection and destruction by the immune system. These include tumor-induced T-cell and NK cell dysfunction, regulatory T-cell and myeloid-derived suppressor cell expansion, M2 phenotypic transformation in glioma-associated macrophages/microglia, upregulation of immunosuppressive glioma cell surface factors and cytokines, tumor microenvironment hypoxia, and iatrogenic sequelae of immunosuppressive treatments. CONCLUSIONS: Gliomas create a profoundly immunosuppressive environment, both locally within the tumor and systemically. Future research should aim to address these immunosuppressive mechanisms in the effort to generate treatment options with meaningful survival benefits for this patient population.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Terapia de Imunossupressão , Macrófagos/imunologia , Microambiente Tumoral
8.
Mol Ther ; 28(12): 2577-2592, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-32755564

RESUMO

T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have produced impressive outcomes for the treatment of B cell malignancies, but different products vary in kinetics, persistence, and toxicity profiles based on the co-stimulatory domains included in the CAR. In this study, we performed transcriptional profiling of bulk CAR T cell populations and single cells to characterize the transcriptional states of human T cells transduced with CD3ζ, 4-1BB-CD3ζ (BBζ), or CD28-CD3ζ (28ζ) co-stimulatory domains at rest and after activation by triggering their CAR or their endogenous T cell receptor (TCR). We identified a transcriptional signature common across CARs with the CD3ζ signaling domain, as well as a distinct program associated with the 4-1BB co-stimulatory domain at rest and after activation. CAR T cells bearing BBζ had increased expression of human leukocyte antigen (HLA) class II genes, ENPP2, and interleukin (IL)-21 axis genes, and decreased PD1 compared to 28ζ CAR T cells. Similar to previous studies, we also found BBζ CAR CD8 T cells to be enriched in a central memory cell phenotype and fatty acid metabolism genes. Our data uncovered transcriptional signatures related to costimulatory domains and demonstrated that signaling domains included in CARs uniquely shape the transcriptional programs of T cells.


Assuntos
Ligante 4-1BB/química , Ligante 4-1BB/metabolismo , Engenharia Celular/métodos , Domínios Proteicos/genética , RNA Citoplasmático Pequeno/genética , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais/genética , Linfócitos T/metabolismo , Transcriptoma , Células HEK293 , Humanos , Células K562 , RNA-Seq/métodos , Análise de Célula Única , Transdução Genética
9.
10.
J Biol Chem ; 295(11): 3431-3446, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32005668

RESUMO

Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP) is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins. Here, we examined the characteristics and covariates of the cancer cell response to DNMDP. On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels. However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression. Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding. Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor-interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP. We determined that AIP is also required for PDE3A-SLFN12 complex formation. Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/patologia , Sequência de Bases , Biomarcadores Tumorais/metabolismo , Sistemas CRISPR-Cas/genética , Domínio Catalítico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/química , Mutação da Fase de Leitura/genética , Genoma , Heterozigoto , Humanos , Ligação Proteica/efeitos dos fármacos , Piridazinas/farmacologia
11.
Clin Cancer Res ; 26(5): 1141-1151, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31744830

RESUMO

PURPOSE: Although pituitary adenoma is classified as benign, Cushing disease is associated with significant morbidity due to the numerous sequelae of elevated cortisol levels. Successful therapy for Cushing disease remains elusive due to high rates of treatment-refractory recurrence. The frequent emergence of lymphocytic hypophysitis following checkpoint blockade for other cancers, as well as the expression of PD-L1 on pituitary adenomas, suggest a role for immunotherapy. EXPERIMENTAL DESIGN: This study confirms PD-L1 expression on functioning pituitary adenomas and is the first to evaluate the efficacy of checkpoint blockade (anti-PD-L1) therapy in a preclinical model of Cushing disease. RESULTS: Herein, treatment with anti-PD-L1 was successful in reducing adrenocorticotropic hormone plasma levels, decreasing tumor growth, and increasing survival in our model. Furthermore, tumor-infiltrating T cells demonstrated a pattern of checkpoint expression similar to other checkpoint blockade-susceptible tumors. CONCLUSIONS: This suggests that immunotherapy, particularly blockade of the PD1/PD-L1 axis, may be a novel therapeutic option for refractory Cushing disease. Clinical investigation is encouraged.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Imunoterapia/métodos , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Linfócitos T/imunologia , Adenoma/tratamento farmacológico , Adenoma/imunologia , Adenoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/imunologia , Hipersecreção Hipofisária de ACTH/patologia , Neoplasias Hipofisárias/imunologia , Neoplasias Hipofisárias/patologia , Taxa de Sobrevida , Adulto Jovem
13.
Clin Cancer Res ; 25(23): 7046-7057, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31439577

RESUMO

PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA approved for the treatment of relapsed or refractory large B-cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging. EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B-cell development that remains highly expressed in several subtypes of B-cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models. RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19+, CD19-, and mixed CD19+/CD19-B-cell lymphoma. CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B-cell lymphomas.


Assuntos
Antígenos CD19/imunologia , Antígenos CD79/imunologia , Imunoterapia Adotiva/métodos , Linfoma de Célula do Manto/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Apoptose , Proliferação de Células , Humanos , Ativação Linfocitária , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Blood ; 132(14): 1495-1506, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30089630

RESUMO

Chimeric antigen receptor (CAR) T cells have emerged as a novel form of treatment of patients with B-cell malignancies. In particular, anti-CD19 CAR T-cell therapy has effected impressive clinical responses in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, not all patients respond, and relapse with antigen loss has been observed in all patient subsets. Here, we report on the design and optimization of a novel CAR directed to the surface antigen CD37, which is expressed in B-cell non-Hodgkin lymphomas, in chronic lymphocytic leukemia, and in some cases of cutaneous and peripheral T-cell lymphomas. We found that CAR-37 T cells demonstrated antigen-specific activation, cytokine production, and cytotoxic activity in models of B- and T-cell lymphomas in vitro and in vivo, including patient-derived xenografts. Taken together, these results are the first showing that T cells expressing anti-CD37 CAR have substantial activity against 2 different lymphoid lineages, without evidence of significant T-cell fratricide. Furthermore, anti-CD37 CARs were readily combined with anti-CD19 CARs to generate dual-specific CAR T cells capable of recognizing CD19 and CD37 alone or in combination. Our findings indicate that CD37-CAR T cells represent a novel therapeutic agent for the treatment of patients with CD37-expressing lymphoid malignancies.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Linfoma de Células T/terapia , Tetraspaninas/imunologia , Animais , Antígenos de Neoplasias/análise , Linhagem Celular Tumoral , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Linfoma de Células T/imunologia , Linfoma de Células T/patologia , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/transplante , Tetraspaninas/análise , Tetraspaninas/antagonistas & inibidores
15.
Mol Microbiol ; 104(3): 499-519, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28187496

RESUMO

The morphological transition of the opportunistic fungal pathogen Candida albicans from budding to hyphal growth has been implicated in its ability to cause disease in animal models. Absence of SR-like RNA-binding protein Slr1 slows hyphal formation and decreases virulence in a systemic candidiasis model, suggesting a role for post-transcriptional regulation in these processes. SR (serine-arginine)-rich proteins influence multiple steps in mRNA metabolism and their localization and function are frequently controlled by modification. We now demonstrate that Slr1 binds to polyadenylated RNA and that its intracellular localization is modulated by phosphorylation and methylation. Wildtype Slr1-GFP is predominantly nuclear, but also co-fractionates with translating ribosomes. The non-phosphorylatable slr1-6SA-GFP protein, in which six serines in SR/RS clusters are substituted with alanines, primarily localizes to the cytoplasm in budding cells. Intriguingly, hyphal cells display a slr1-6SA-GFP focus at the tip near the Spitzenkörper, a vesicular structure involved in molecular trafficking to the tip. The presence of slr1-6SA-GFP hyphal tip foci is reduced in the absence of the mRNA-transport protein She3, suggesting that unphosphorylated Slr1 associates with mRNA-protein complexes transported to the tip. The impact of SLR1 deletion on hyphal formation and function thus may be partially due to a role in hyphal mRNA transport.


Assuntos
Candida albicans/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA/metabolismo , Candida albicans/genética , Candida albicans/crescimento & desenvolvimento , Citoplasma/metabolismo , Proteínas Fúngicas/metabolismo , Deleção de Genes , Hifas/genética , Hifas/crescimento & desenvolvimento , Hifas/metabolismo , Fosforilação , RNA Mensageiro/metabolismo
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