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2.
Immunity ; 52(1): 183-199.e9, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31924475

RESUMO

Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional profiles of 131,224 single cells from peripheral and intra-tumoral immune populations from patients with HPV- and HPV+ HNSCC and healthy donors. Immune cells within tumors of HPV- and HPV+ HNSCC displayed a spectrum of transcriptional signatures, with helper CD4+ T cells and B cells being relatively divergent and CD8+ T cells and CD4+ regulatory T cells being relatively similar. Transcriptional results were contextualized through multispectral immunofluorescence analyses and evaluating putative cell-cell communication based on spatial proximity. These analyses defined a gene expression signature associated with CD4+ T follicular helper cells that is associated with longer progression-free survival in HNSCC patients. The datasets and analytical approaches herein provide a resource for the further study of the impact of immune cells on viral- and carcinogen-induced cancers.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Alphapapillomavirus/imunologia , Diferenciação Celular/imunologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imunoterapia , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
3.
Proc Natl Acad Sci U S A ; 116(48): 24231-24241, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31699819

RESUMO

Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)-stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A-D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.

4.
Semin Immunol ; 42: 101305, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31604537

RESUMO

Immune checkpoint therapy has revolutionized cancer treatment by blocking inhibitory pathways in T cells that limits the an effective anti-tumor immune response. Therapeutics targeting CTLA-4 and PD1/PDL1 have progressed to first line therapy in multiple tumor types with some patients exhibiting tumor regression or remission. However, the majority of patients do not benefit from checkpoint therapy emphasizing the need for alternative therapeutic options. Lymphocyte Activation Gene 3 (LAG3) or CD223 is expressed on multiple cell types including CD4+ and CD8+ T cells, and Tregs, and is required for optimal T cell regulation and homeostasis. Persistent antigen-stimulation in cancer or chronic infection leads to chronic LAG3 expression, promoting T cell exhaustion. Targeting LAG3 along with PD1 facilitates T cell reinvigoration. A substantial amount of pre-clinical data and mechanistic analysis has led to LAG3 being the third checkpoint to be targeted in the clinic with nearly a dozen therapeutics under investigation. In this review, we will discuss the structure, function and role of LAG3 in murine and human models of disease, including autoimmune and inflammatory diseases, chronic viral and parasitic infections, and cancer, emphasizing new advances in the development of LAG3-targeting immunotherapies for cancer that are currently in clinical trials.

5.
Nat Immunol ; 20(6): 724-735, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30936494

RESUMO

Regulatory T cells (Treg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Treg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here, we found that the cytokines IL-10 and IL-35 (Ebi3-IL-12α heterodimer) were divergently expressed by Treg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating several inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8+ TILs. While expression of BLIMP1 (encoded by Prdm1) was a common target, IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for Treg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8+ TILs that limits effective anti-tumor immunity.


Assuntos
Imunidade Celular , Interleucina-10/metabolismo , Interleucinas/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transferência Adotiva , Animais , Citocinas/genética , Citocinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Melanoma Experimental , Camundongos , Neoplasias/patologia , Transdução de Sinais , Transcriptoma
6.
Nat Commun ; 10(1): 1649, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967541

RESUMO

The recently developed droplet-based single-cell transcriptome sequencing (scRNA-seq) technology makes it feasible to perform a population-scale scRNA-seq study, in which the transcriptome is measured for tens of thousands of single cells from multiple individuals. Despite the advances of many clustering methods, there are few tailored methods for population-scale scRNA-seq studies. Here, we develop a Bayesian mixture model for single-cell sequencing (BAMM-SC) method to cluster scRNA-seq data from multiple individuals simultaneously. BAMM-SC takes raw count data as input and accounts for data heterogeneity and batch effect among multiple individuals in a unified Bayesian hierarchical model framework. Results from extensive simulation studies and applications of BAMM-SC to in-house experimental scRNA-seq datasets using blood, lung and skin cells from humans or mice demonstrate that BAMM-SC outperformed existing clustering methods with considerable improved clustering accuracy, particularly in the presence of heterogeneity among individuals.


Assuntos
Biologia Computacional/métodos , Análise de Dados , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Animais , Teorema de Bayes , Biópsia , Análise por Conglomerados , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica/métodos , Voluntários Saudáveis , Humanos , Leucócitos Mononucleares , Pulmão/citologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pele/citologia , Pele/patologia , Software , Transcriptoma/genética
7.
Mol Cancer Res ; 17(1): 131-139, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30143553

RESUMO

Tryptophan catabolism is an attractive target for reducing tumor progression and improving antitumor immunity in multiple cancers. Tumor infiltration by CD8 T cells correlates with improved prognosis in triple-negative breast cancer (TNBC) and a significant effort is underway to improve CD8 T-cell antitumor activity. In this study, primary human immune cells were isolated from the peripheral blood of patients and used to demonstrate that the tryptophan catabolite kynurenine induces CD8 T-cell death. Furthermore, it is demonstrated that anchorage-independent TNBC utilizes the tryptophan-catabolizing enzyme tryptophan 2,3-dioxygenase (TDO) to inhibit CD8 T-cell viability. Publicly available data revealed that high TDO2, the gene encoding TDO, correlates with poor breast cancer clinical outcomes, including overall survival and distant metastasis-free survival, while expression of the gene encoding the more commonly studied tryptophan-catabolizing enzyme, IDO1 did not. Metabolomic analysis, using quantitative mass spectrometry, of tryptophan and its catabolites, including kynurenine, in the plasma from presurgical breast cancer patients (n = 77) and 40 cancer-free donors (n = 40) indicated a strong correlation between substrate and catabolite in both groups. Interestingly, both tryptophan and kynurenine were lower in the plasma from patients with breast cancer compared with controls, particularly in women with estrogen receptor (ER)-negative and stage III and IV breast cancer. IMPLICATIONS: This study underscores the importance of tryptophan catabolism, particularly in aggressive disease, and suggests that future pharmacologic efforts should focus on developing drugs that target both TDO and IDO1.


Assuntos
Neoplasias da Mama/sangue , Linfócitos T CD8-Positivos/enzimologia , Triptofano Oxigenase/sangue , Triptofano/sangue , Neoplasias da Mama/enzimologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Cinurenina/farmacologia , Linfócitos do Interstício Tumoral/enzimologia , Linfócitos do Interstício Tumoral/imunologia , Triptofano Oxigenase/imunologia
9.
J Proteomics ; 176: 13-23, 2018 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-29331515

RESUMO

To build a catalog of peptides presented by breast cancer cells, we undertook systematic MHC class I immunoprecipitation followed by elution of MHC class I-loaded peptides in breast cancer cells. We determined the sequence of 3196 MHC class I ligands representing 1921 proteins from a panel of 20 breast cancer cell lines. After removing duplicate peptides, i.e., the same peptide eluted from more than one cell line, the total number of unique peptides was 2740. Of the unique peptides eluted, more than 1750 had been previously identified, and of these, sixteen have been shown to be immunogenic. Importantly, half of these immunogenic peptides were shared between different breast cancer cell lines. MHC class I binding probability was used to plot the distribution of the eluted peptides in accordance with the binding score for each breast cancer cell line. We also determined that the tested breast cancer cells presented 89 mutation-containing peptides and peptides derived from aberrantly translated genes, 7 of which were shared between four or two different cell lines. Overall, the high throughput identification of MHC class I-loaded peptides is an effective strategy for systematic characterization of cancer peptides, and could be employed for design of multi-peptide anticancer vaccines. SIGNIFICANCE: By employing proteomic analyses of eluted peptides from breast cancer cells, the current study has built an initial HLA-I-typed antigen collection for breast cancer research. It was also determined that immunogenic epitopes can be identified using established cell lines and that shared immunogenic peptides can be found in different cancer types such as breast cancer and leukemia. Importantly, out of 3196 eluted peptides that included duplicate peptides in different cells 89 peptides either contained mutation in their sequence or were derived from aberrant translation suggesting that mutation-containing epitopes are on the order of 2-3% in breast cancer cells. Finally, our results suggest that interfering with MHC class I function is one of the mechanisms of how tumor cells escape immune system attack.


Assuntos
Neoplasias da Mama/imunologia , Antígenos de Histocompatibilidade Classe I/análise , Sequência de Aminoácidos , Apresentação do Antígeno , Antígenos de Neoplasias , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Epitopos/genética , Antígenos HLA , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Mutação , Proteômica/métodos
10.
Cancer Immunol Res ; 5(10): 898-907, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28848053

RESUMO

Effective immunotherapy options for patients with non-small cell lung cancer (NSCLC) are becoming increasingly available. The immunotherapy focus has been on tumor-infiltrating T cells (TILs); however, tumor-infiltrating B cells (TIL-Bs) have also been reported to correlate with NSCLC patient survival. The function of TIL-Bs in human cancer has been understudied, with little focus on their role as antigen-presenting cells and their influence on CD4+ TILs. Compared with other immune subsets detected in freshly isolated primary tumors from NSCLC patients, we observed increased numbers of intratumoral B cells relative to B cells from tumor-adjacent tissues. Furthermore, we demonstrated that TIL-Bs can efficiently present antigen to CD4+ TILs and alter the CD4+ TIL phenotype using an in vitro antigen-presentation assay. Specifically, we identified three CD4+ TIL responses to TIL-Bs, which we categorized as activated, antigen-associated, and nonresponsive. Within the activated and antigen-associated CD4+ TIL population, activated TIL-Bs (CD19+CD20+CD69+CD27+CD21+) were associated with an effector T-cell response (IFNγ+ CD4+ TILs). Alternatively, exhausted TIL-Bs (CD19+CD20+CD69+CD27-CD21-) were associated with a regulatory T-cell phenotype (FoxP3+ CD4+ TILs). Our results demonstrate a new role for TIL-Bs in NSCLC tumors in their interplay with CD4+ TILs in the tumor microenvironment, establishing them as a potential therapeutic target in NSCLC immunotherapy. Cancer Immunol Res; 5(10); 898-907. ©2017 AACR.


Assuntos
Apresentação do Antígeno/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Células Apresentadoras de Antígenos/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores , Linfócitos T CD4-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Imunofenotipagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Microambiente Tumoral/imunologia
11.
Cell ; 169(6): 1130-1141.e11, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552348

RESUMO

Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1-/-) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1-/- Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.


Assuntos
Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Interferon gama/imunologia , Melanoma/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neuropilina-1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Microambiente Tumoral
12.
J Immunol ; 197(4): 1477-88, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27371726

RESUMO

Mechanisms of self-tolerance often result in CD8(+) tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a transplantable colon carcinoma model, we found that CD8(+) T cells became tolerized in <24 h in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8(+) T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first molecular profile of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Experimentais/imunologia , Evasão Tumoral/imunologia , Animais , Separação Celular , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos
13.
Proc Natl Acad Sci U S A ; 113(29): 8272-7, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27307436

RESUMO

Infiltration of T cells in breast tumors correlates with improved survival of patients with breast cancer, despite relatively few mutations in these tumors. To determine if T-cell specificity can be harnessed to augment immunotherapies of breast cancer, we sought to identify the alpha-beta paired T-cell receptors (TCRs) of tumor-infiltrating lymphocytes shared between multiple patients. Because TCRs function as heterodimeric proteins, we used an emulsion-based RT-PCR assay to link and amplify TCR pairs. Using this assay on engineered T-cell hybridomas, we observed ∼85% accurate pairing fidelity, although TCR recovery frequency varied. When we applied this technique to patient samples, we found that for any given TCR pair, the dominant alpha- or beta-binding partner comprised ∼90% of the total binding partners. Analysis of TCR sequences from primary tumors showed about fourfold more overlap in tumor-involved relative to tumor-free sentinel lymph nodes. Additionally, comparison of sequences from both tumors of a patient with bilateral breast cancer showed 10% overlap. Finally, we identified a panel of unique TCRs shared between patients' tumors and peripheral blood that were not found in the peripheral blood of controls. These TCRs encoded a range of V, J, and complementarity determining region 3 (CDR3) sequences on the alpha-chain, and displayed restricted V-beta use. The nucleotides encoding these shared TCR CDR3s varied, suggesting immune selection of this response. Harnessing these T cells may provide practical strategies to improve the shared antigen-specific response to breast cancer.


Assuntos
Neoplasias da Mama/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/metabolismo , Sequência de Bases , Linhagem Celular , Emulsões , Feminino , Humanos , Reação em Cadeia da Polimerase/métodos
14.
Head Neck ; 37(8): 1088-95, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24710745

RESUMO

BACKGROUND: Treatment with a blocking programmed death-1 (αPD-1) antibody recently showed clinical efficacy for various tumor types. In this study, we characterized the expression profile of PD-1/programmed death-ligand-1 (PD-L1) and the potential of PD-1 blockade in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). METHODS: Lymphocytes from peripheral blood, draining lymph nodes, and the tumor were phenotyped for PD-1 expression, and their proliferative activity was assessed in the presence of blocking αPD-1 treatment. Primary tumor expression of PD-L1 was also analyzed using immunohistochemistry (IHC). RESULTS: Lymphocyte PD-1 expression was abundant with highest expression in the tumor, and in vitro mixed lymphocyte reaction demonstrated that PD-1 blockade could induce T cell proliferation. Furthermore, tumor cells were found to have 3 distinct patterns of PD-L1 expression with over 78% of the specimens demonstrating strong PD-L1 positivity. CONCLUSION: Our data strongly supports the use of αPD-1 blockade in patients with HPV-negative HNSCC that are refractory to standard treatments.


Assuntos
Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Papillomaviridae , Receptor de Morte Celular Programada 1/imunologia , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Antígenos CD4/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Técnicas In Vitro/métodos , Fenótipo , Valor Preditivo dos Testes , Receptor de Morte Celular Programada 1/genética , Sensibilidade e Especificidade , Transcriptoma , Células Tumorais Cultivadas
15.
J Pathol ; 235(3): 478-89, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25348195

RESUMO

Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate-derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1-infected mice were characterized at 8 weeks post-infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi-Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression.


Assuntos
Adenocarcinoma/patologia , Progressão da Doença , Escherichia coli/fisiologia , Próstata/microbiologia , Próstata/patologia , Neoplasias da Próstata/patologia , Microambiente Tumoral/fisiologia , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Animais , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Escherichia coli/isolamento & purificação , Humanos , Hiperplasia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/fisiopatologia , Prostatite/metabolismo , Prostatite/patologia , Prostatite/fisiopatologia , Receptores Androgênicos/metabolismo , Células Th17/patologia
16.
Int J Radiat Oncol Biol Phys ; 87(4): 769-76, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24064321

RESUMO

PURPOSE: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. METHODS AND MATERIALS: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. RESULTS: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. CONCLUSIONS: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.


Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/uso terapêutico , Tomografia Computadorizada de Feixe Cônico/métodos , Imunoterapia Adotiva/métodos , Radioterapia Conformacional/métodos , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Transferência Adotiva/métodos , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Terapia Combinada/métodos , Terapia Combinada/mortalidade , Hemaglutininas/imunologia , Hemaglutininas/metabolismo , Imunoterapia Adotiva/mortalidade , Linfócitos do Interstício Tumoral/citologia , Masculino , Camundongos , Camundongos Transgênicos , Gradação de Tumores , Micrometástase de Neoplasia/prevenção & controle , Órgãos em Risco/diagnóstico por imagem , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Cintilografia , Dosagem Radioterapêutica , Radioterapia Conformacional/mortalidade , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Reguladores/citologia , Carga Tumoral , Bexiga Urinária/diagnóstico por imagem
17.
J Transl Med ; 11: 89, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23557194

RESUMO

BACKGROUND: The FDA recently approved an anti-CTLA-4 antibody (Iplimumab) for the treatment of metastatic melanoma. This decision was based on Phase III results, which demonstrate that blocking this immune checkpoint provides a survival advantage in patients with advanced disease. As a single agent, ipilimumab is also being clinically evaluated in advanced (metastatic, castrate-resistant) prostate cancer and two randomized, placebo-controlled Phase III studies have recently completed accrual. METHODS: We used a well-described genetically engineered mouse (GEM), autochronous prostate cancer model (Pro-TRAMP) to explore the relative sequencing and dosing of anti-CTLA-4 antibody when combined with a cell-based, GM-CSF-secreting vaccine (GVAX). RESULTS: Our results show that combined treatment results in a dramatic increase in effector CD8 T cells in the prostate gland, and enhanced tumor-antigen directed lytic function. These effects are maximized when CTLA-4 blockade is applied after, but not before, vaccination. Additional experiments, using models of metastatic disease, show that incorporation of low-dose cyclophosphamide into this combined treatment regimen results in an additional pre-clinical benefit. CONCLUSIONS: Together these studies define a combination regimen using anti-CTLA-4/GVAX immunotherapy and low-dose chemotherapy for potential translation to a clinical trial setting.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia/métodos , Neoplasias da Próstata/terapia , Animais , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/citologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Ciclofosfamida/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Ipilimumab , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica , Neoplasias da Próstata/imunologia , Fatores de Tempo
18.
Cancer Res ; 73(6): 1733-41, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23288508

RESUMO

Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We show membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor-associated macrophages is geographically localized to sites of lymphocyte fronts, whereas the majority of CD8+ tumor-infiltrating lymphocytes express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for IFN-γ, a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.


Assuntos
Antígeno B7-H1/fisiologia , Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Papillomaviridae/isolamento & purificação , Receptor de Morte Celular Programada 1/fisiologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/virologia , Citometria de Fluxo , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imuno-Histoquímica , Interferon gama/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Immunol Res ; 55(1-3): 22-33, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22941561

RESUMO

There will be over half a million cancer-related deaths in the United States in 2012, with lung cancer being the leader followed by prostate in men and breast in women. There is estimated to be more than one and a half million new cases of cancer in 2012, making the development of effective therapies a high priority. As tumor immunologists, we are interested in the development of immunotherapies because the immune response offers exquisite specificity and the potential to target tumor cells without harming normal cells. In this review, we highlight the current advances in the field of immunotherapy and the current work being completed by laboratories at University of Colorado School of Medicine in multiple malignancies, including breast cancer, lung cancer, melanoma, thyroid cancer, and glioblastoma. This work focuses on augmenting the anti-tumor response of CD8 T cells in the blood, lymph nodes, and tumors of patients, determining biomarkers for patients who are more likely to respond to immunotherapy, and identifying additional anti-tumor and immunosuppressive cells that influence the overall response to tumors. These collaborative efforts will identify mechanisms to improve immune function, which may elucidate therapeutic targets for clinical trials to improve patient health and survival.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias/imunologia , Colorado , Humanos , Imunoterapia , Neoplasias/terapia , Universidades
20.
PLoS One ; 7(3): e34547, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22479644

RESUMO

Helios, an Ikaros family transcription factor, is preferentially expressed at the mRNA and protein level in regulatory T cells. Helios expression previously appeared to be restricted to thymic-derived Treg. Consistent with recent data, we show here that Helios expression is inducible in vitro under certain conditions. To understand phenotypic and functional differences between Helios(+) and Helios(-) Treg, we profiled cell-surface markers of FoxP3(+) Treg using unmanipulated splenocytes. We found that CD103 and GITR are expressed at high levels on a subset of Helios(+) Treg and that a Helios(+) Treg population could be significantly enriched by FACS sorting using these two markers. Quantitative real-time PCR (qPCR) analysis revealed increased TGF-ß message in Helios(+) Treg, consistent with the possibility that this population possesses enhanced regulatory potential. In tumor-bearing mice, we found that Helios(+) Treg were relatively over-represented in the tumor-mass, and BrdU studies showed that, in vivo, Helios(+) Treg proliferated more than Helios(-) Treg. We hypothesized that Helios-enriched Treg might exert increased suppressive effects. Using in vitro suppression assays, we show that Treg function correlates with the absolute number of Helios(+) cells in culture. Taken together, these data show that Helios(+) Treg represent a functional subset with associated CD103 and GITR expression.


Assuntos
Proteínas de Ligação a DNA/genética , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/genética , Animais , Antígenos CD/genética , Regulação Neoplásica da Expressão Gênica , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Cadeias alfa de Integrinas/genética , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/genética , Fenótipo , Baço/citologia , Linfócitos T Reguladores/citologia , Regulação para Cima
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