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1.
Cancer Discov ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794959

RESUMO

Immunotherapies aimed at alleviating the inhibitory constraints on Tcells have revolutionised cancer management. To date, these have focused on the blockade of cell surface checkpoints such as PD-1. Herein we identify protein-tyrosine-phosphatase-1B (PTP1B) as an intracellular checkpoint that is upregulated in T cells in tumors. We show that the increased PTP1B limits T cell expansion and cytotoxicity to contribute to tumor growth. T cell-specific PTP1B deletion increased STAT-5 signaling and this enhanced the antigen-induced expansion and cytotoxicity of CD8+ T cells to suppress tumor growth. The pharmacological inhibition of PTP1B recapitulated the T cell-mediated repression of tumor growth and enhanced the response to PD-1 blockade. Furthermore, the deletion or inhibition of PTP1B enhanced the efficacy of adoptively-transferred chimeric-antigen-receptor (CAR) T cells against solid tumors. Our findings identify PTP1B as an intracellular checkpoint whose inhibition can alleviate the inhibitory constraints on T cells and CAR T cells to combat cancer.

2.
Cancer Cell ; 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34739846

RESUMO

In this issue of Cancer Cell, Xue et al. demonstrate that adoptive transfer of tumor-specific Th9 cells can eradicate established tumors containing antigen-loss-variant cells (ALVs) through both direct killing and bystander effects mediated by intratumoral accumulation of extracellular ATP (eATP) that promotes monocyte infiltration and stimulation of IFNα/ß production.

3.
Nat Commun ; 12(1): 4746, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362900

RESUMO

The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.


Assuntos
Imunidade Celular , Células Matadoras Naturais/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Neoplasias/imunologia , Animais , Antineoplásicos , Linhagem Celular Tumoral , Citocinas , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Metástase Neoplásica , Neoplasias/patologia
4.
Cancer Cell ; 39(7): 885-888, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34256903

RESUMO

CAR T cell therapy successes are challenged by several mechanisms of resistance including the development of dysfunctional states such as exhaustion. The features of CAR T cell exhaustion, its role in limiting the efficacy of CAR T therapy in both liquid and solid malignancies, and potential strategies to overcome it are discussed.

5.
Cancer Discov ; 11(10): 2582-2601, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33990344

RESUMO

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity. SIGNIFICANCE: Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer.This article is highlighted in the In This Issue feature, p. 2355.

7.
Nat Commun ; 12(1): 3236, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050151

RESUMO

Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptor A2A de Adenosina/genética , Linfócitos T/transplante , Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Sistemas CRISPR-Cas/genética , Engenharia Celular/métodos , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Edição de Genes , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/imunologia , RNA Interferente Pequeno/metabolismo , RNA-Seq , Receptor A2A de Adenosina/metabolismo , Receptor ErbB-2/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/genética
8.
Nat Rev Immunol ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879873

RESUMO

The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells - namely, chimeric antigen receptor T cells - that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers.

11.
Nat Rev Drug Discov ; 19(11): 776-800, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32929243

RESUMO

Dysregulation of the epigenome drives aberrant transcriptional programmes that promote cancer onset and progression. Although defective gene regulation often affects oncogenic and tumour-suppressor networks, tumour immunogenicity and immune cells involved in antitumour responses may also be affected by epigenomic alterations. This could have important implications for the development and application of both epigenetic therapies and cancer immunotherapies, and combinations thereof. Here, we review the role of key aberrant epigenetic processes - DNA methylation and post-translational modification of histones - in tumour immunogenicity, as well as the effects of epigenetic modulation on antitumour immune cell function. We emphasize opportunities for small-molecule inhibitors of epigenetic regulators to enhance antitumour immune responses, and discuss the challenges of exploiting the complex interplay between cancer epigenetics and cancer immunology to develop treatment regimens combining epigenetic therapies with immunotherapies.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/terapia , Animais , Epigenômica/métodos , Humanos , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
12.
Cancer Res ; 80(19): 4129-4144, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32816860

RESUMO

Therapeutic checkpoint antibodies blocking programmed death receptor 1/programmed death ligand 1 (PD-L1) signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intratumoral copper levels influence PD-L1 expression in cancer cells. Deep analysis of the The Cancer Genome Atlas database and tissue microarrays showed strong correlation between the major copper influx transporter copper transporter 1 (CTR-1) and PD-L1 expression across many cancers but not in corresponding normal tissues. Copper supplementation enhanced PD-L1 expression at mRNA and protein levels in cancer cells and RNA sequencing revealed that copper regulates key signaling pathways mediating PD-L1-driven cancer immune evasion. Conversely, copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1. Copper-chelating drugs also significantly increased the number of tumor-infiltrating CD8+ T and natural killer cells, slowed tumor growth, and improved mouse survival. Overall, this study reveals an important role for copper in regulating PD-L1 and suggests that anticancer immunotherapy might be enhanced by pharmacologically reducing intratumor copper levels. SIGNIFICANCE: These findings characterize the role of copper in modulating PD-L1 expression and contributing to cancer immune evasion, highlighting the potential for repurposing copper chelators as enhancers of antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4129/F1.large.jpg.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/imunologia , Cobre/metabolismo , Neuroblastoma/imunologia , Evasão Tumoral/fisiologia , Animais , Antígeno B7-H1/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Quelantes/farmacologia , Transportador de Cobre 1/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Células Matadoras Naturais , Linfócitos do Interstício Tumoral/patologia , Camundongos Endogâmicos BALB C , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Trietilenofosforamida/farmacologia , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Mol Ther ; 28(11): 2379-2393, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-32735774

RESUMO

Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR T cells in solid tumors is limited by tumor-induced immunosuppression, leading to the development of combination approaches, such as adjuvant programmed cell death 1 (PD-1) blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whereas different cytokine preconditioning milieu, such as IL-7/IL-15, have been shown to promote T cell engraftment, the impact of this approach on CAR T cell responses to adjuvant immune-checkpoint blockade has not been assessed. In the current study, we reveal that the preconditioning of CAR T cells with IL-7/IL-15 increased CAR T cell responses to anti-PD-1 adjuvant therapy. This was associated with the emergence of an intratumoral CD8+CD62L+TCF7+IRF4- population that was highly responsive to anti-PD-1 therapy and mediated the vast majority of transcriptional and epigenetic changes in vivo following PD-1 blockade. Our data indicate that preservation of CAR T cells in a TCF7+ phenotype is crucial for their responsiveness to adjuvant immunotherapy approaches and should be a key consideration when designing clinical protocols.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva , Interleucina-15/administração & dosagem , Neoplasias/terapia , Biomarcadores Tumorais , Terapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/etiologia , Resultado do Tratamento
14.
Curr Opin Pharmacol ; 53: 91-97, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32854024

RESUMO

Adoptive cellular therapy involves the ex vivo expansion of immune cells, conventionally T cells, before reinfusion back to the patient. Variations in adoptive cellular therapy include transduction of a patient's T cells with either a transgenic T cell receptor or chimeric antigen receptor (CAR) to recognize a defined tumor antigen. Given that adenosine is a major axis of immunosuppression of T cells, particularly in hypoxic tumor microenvironments, therapeutics targeting this pathway are currently being assessed for their potential to enhance adoptive T cell therapies. The use of gene-editing technology, commonly used in tandem with CAR and transgenic T cell receptor (TCR) based adoptive cellular therapy, offers further opportunities to specifically modulate responses to adenosine. This review will discuss recent advances in targeting the adenosine pathway for enhancing the effectiveness of adoptive cellular therapy in the treatment of solid cancers.


Assuntos
Adenosina/imunologia , Edição de Genes , Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos , Animais , Humanos , Neoplasias/genética , Neoplasias/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
16.
Cancer Cell ; 37(6): 756-758, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32516586

RESUMO

In this issue of Cancer Cell, Gurusamy et al. use a CRISPR-Cas9 screening approach to demonstrate that deletion of p38 increases multiple phenotypic qualities of effective anti-tumor T cells. Preconditioning T cells with a p38 inhibitor enhances anti-tumor efficacy of adoptive immunotherapy.


Assuntos
Imunoterapia Adotiva , Linfócitos T , Sistemas CRISPR-Cas , Edição de Genes , Fenótipo
17.
Nat Immunol ; 21(8): 914-926, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32424363

RESUMO

Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.


Assuntos
Células Dendríticas/imunologia , Imunoterapia Adotiva , Proteínas de Membrana/imunologia , Neoplasias Experimentais/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Humanos , Fatores Imunológicos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia
18.
Am Soc Clin Oncol Educ Book ; 40: 1-6, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32412805

RESUMO

A common pathway for an effective immune anticancer response involves recognition of tumor neoantigens and subsequent targeting of cancer cells by T cells. In this article, we provide an overview of the current status of two approaches to directly enhance this interaction using either adoptive cell therapy or personalized cancer vaccines with focus on recent advances in solid tumors, including lung cancer.


Assuntos
Vacinas Anticâncer , Terapia Baseada em Transplante de Células e Tecidos , Imunoterapia , Neoplasias/terapia , Humanos , Linfócitos do Interstício Tumoral/transplante , Neoplasias/imunologia , Medicina de Precisão , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos
19.
Nat Rev Clin Oncol ; 17(6): 341-348, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32112054

RESUMO

The presence of tumour-infiltrating lymphocytes (TILs) is associated with favourable outcomes in patients with breast cancer as well as in those with other solid tumours. T cells make up a considerable proportion of TILs and current evidence suggests that CD8+ T cells are a crucial determinant of favourable clinical outcomes. Studies involving tumour material from numerous solid tumour types, including breast cancer, demonstrate that the CD8+ TILs include a subpopulation of tissue-resident memory T (TRM) cells. This subpopulation has features consistent with those of TRM cells, which have been described as having a role in peripheral immune surveillance and viral immunity in both humans and mice. Patients with early-stage triple-negative breast cancers harbouring greater numbers of TRM cells have a substantially improved prognosis and longer overall survival. Furthermore, patients with advanced-stage breast cancers with higher levels of TRM cells have increased response rates to anti-PD-1 antibodies. These findings have motivated efforts to explore whether CD8+ TRM cells include tumour-specific T cells, their functional responses to cognate antigens and their role in responses to immune checkpoint inhibition. In this Review, we focus on the clinical significance of CD8+ TRM cells and the potential ways that these cells can be targeted to improve the success of immunotherapeutic approaches in patients with breast cancer, as well as in those with other solid tumour types.


Assuntos
Neoplasias da Mama/imunologia , Memória Imunológica/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos , Humanos , Vigilância Imunológica , Imunoterapia Adotiva , Receptor ErbB-2/metabolismo , Subpopulações de Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/terapia
20.
J Immunol ; 204(8): 2308-2315, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32152070

RESUMO

CRISPR/Cas9 technologies have revolutionized our understanding of gene function in complex biological settings, including T cell immunology. Current CRISPR-mediated gene editing strategies in T cells require in vitro stimulation or culture that can both preclude the study of unmanipulated naive T cells and alter subsequent differentiation. In this study, we demonstrate highly efficient gene editing within uncultured primary naive murine CD8+ T cells by electroporation of recombinant Cas9/sgRNA ribonucleoprotein immediately prior to in vivo adoptive transfer. Using this approach, we generated single and double gene knockout cells within multiple mouse infection models. Strikingly, gene deletion occurred even when the transferred cells were left in a naive state, suggesting that gene deletion occurs independent of T cell activation. Finally, we demonstrate that targeted mutations can be introduced into naive CD8+ T cells using CRISPR-based homology-directed repair. This protocol thus expands CRISPR-based gene editing approaches beyond models of robust T cell activation to encompass both naive T cell homeostasis and models of weak activation, such as tolerance and tumor models.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Edição de Genes , Animais , Sistemas CRISPR-Cas/imunologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/imunologia , Eletroporação , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/imunologia
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