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Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease.

PubMed - Tue, 10/24/2017 - 11:31
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Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease.

Nat Rev Immunol. 2016 Mar;16(3):149-63

Authors: DuPage M, Bluestone JA

Abstract
CD4(+) T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4(+) T cell plasticity by examining the molecular mechanisms that regulate it - from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

PMID: 26875830 [PubMed - indexed for MEDLINE]

Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses.

PubMed - Tue, 10/24/2017 - 11:31
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Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses.

Immunity. 2015 Sep 15;43(3):579-90

Authors: Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, DuPage M, Tammela T, Kerper NR, Farago AF, Robbins R, Crowley DM, Bronson RT, Jacks T

Abstract
Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs have been described in human lung cancers, but their function remains to be determined. TLSs in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen-presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLSs upon Treg cell depletion, leading to tumor destruction. Thus, we propose that Treg cells in TA-TLSs can inhibit endogenous immune responses against tumors, and targeting these cells might provide therapeutic benefit for cancer patients.

PMID: 26341400 [PubMed - indexed for MEDLINE]

The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation.

PubMed - Tue, 10/24/2017 - 11:31
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The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation.

Immunity. 2015 Feb 17;42(2):227-238

Authors: DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, Zhang R, Turka L, Marson A, Bluestone JA

Abstract
Regulatory T cells (Treg cells) are required for immune homeostasis. Chromatin remodeling is essential for establishing diverse cellular identities, but how the epigenetic program in Treg cells is maintained throughout the dynamic activation process remains unclear. Here we have shown that CD28 co-stimulation, an extracellular cue intrinsically required for Treg cell maintenance, induced the chromatin-modifying enzyme, Ezh2. Treg-specific ablation of Ezh2 resulted in spontaneous autoimmunity with reduced Foxp3(+) cells in non-lymphoid tissues and impaired resolution of experimental autoimmune encephalomyelitis. Utilizing a model designed to selectively deplete wild-type Treg cells in adult mice co-populated with Ezh2-deficient Treg cells, Ezh2-deficient cells were destabilized and failed to prevent autoimmunity. After activation, the transcriptome of Ezh2-deficient Treg cells was disrupted, with altered expression of Treg cell lineage genes in a pattern similar to Foxp3-deficient Treg cells. These studies reveal a critical role for Ezh2 in the maintenance of Treg cell identity during cellular activation.

PMID: 25680271 [PubMed - indexed for MEDLINE]

Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability.

PubMed - Tue, 10/24/2017 - 11:31
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Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability.

Nat Immunol. 2015 Feb;16(2):188-96

Authors: Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, Bluestone JA, Turka LA

Abstract
Foxp3(+) regulatory T cells (Treg cells) are required for immunological homeostasis. One notable distinction between conventional T cells (Tconv cells) and Treg cells is differences in the activity of phosphatidylinositol-3-OH kinase (PI(3)K); only Tconv cells downregulate PTEN, the main negative regulator of PI(3)K, upon activation. Here we found that control of PI(3)K in Treg cells was essential for lineage homeostasis and stability. Mice lacking Pten in Treg cells developed an autoimmune-lymphoproliferative disease characterized by excessive T helper type 1 (TH1) responses and B cell activation. Diminished control of PI(3)K activity in Treg cells led to reduced expression of the interleukin-2 (IL-2) receptor α subunit CD25, accumulation of Foxp3(+)CD25(-) cells and, ultimately, loss of expression of the transcription factor Foxp3 in these cells. Collectively, our data demonstrate that control of PI(3)K signaling by PTEN in Treg cells is critical for maintaining their homeostasis, function and stability.

PMID: 25559257 [PubMed - indexed for MEDLINE]

Genetically engineered mouse models of cancer reveal new insights about the antitumor immune response.

PubMed - Tue, 10/24/2017 - 11:31
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Genetically engineered mouse models of cancer reveal new insights about the antitumor immune response.

Curr Opin Immunol. 2013 Apr;25(2):192-9

Authors: DuPage M, Jacks T

Abstract
Cancer is a complex disease that can originate in virtually all the tissues of the body, and tumors progress through many different stages during their development. While genetic mutations in the emerging cancer cells drive this disease, it has become increasingly clear that cancer development is strongly influenced by the surrounding microenvironment. Cells of the immune system are critical components of this extrinsic network of cancer regulators, contributing significantly to the microenvironment of most cancers and either promoting or inhibiting the initiation and progression of this disease. Genetically engineered mouse (GEM) mouse models of spontaneous cancer are starting to shape our understanding of how antitumor T cells may act to prevent or inhibit cancer progression in some settings and not others. Lessons learned from investigating spontaneous mouse cancer models have important implications for directing clinical efforts that attempt to direct a cancer patient's immune system to eradicate their disease.

PMID: 23465466 [PubMed - indexed for MEDLINE]

Expression of tumour-specific antigens underlies cancer immunoediting.

PubMed - Tue, 10/24/2017 - 11:31
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Expression of tumour-specific antigens underlies cancer immunoediting.

Nature. 2012 Feb 08;482(7385):405-9

Authors: DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T

Abstract
Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced. However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours. Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.

PMID: 22318517 [PubMed - indexed for MEDLINE]

Suppression of lung adenocarcinoma progression by Nkx2-1.

PubMed - Tue, 10/24/2017 - 11:31
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Suppression of lung adenocarcinoma progression by Nkx2-1.

Nature. 2011 May 05;473(7345):101-4

Authors: Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, Hubbard DD, DuPage MJ, Whittaker CA, Hoersch S, Yoon S, Crowley D, Bronson RT, Chiang DY, Meyerson M, Jacks T

Abstract
Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumours are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 (also called Ttf-1 or Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically restricted chromatin regulator Hmga2. Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor.

PMID: 21471965 [PubMed - indexed for MEDLINE]

Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression.

PubMed - Tue, 10/24/2017 - 11:31
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Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression.

Cancer Cell. 2011 Jan 18;19(1):72-85

Authors: DuPage M, Cheung AF, Mazumdar C, Winslow MM, Bronson R, Schmidt LM, Crowley D, Chen J, Jacks T

Abstract
Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here, we describe a system to introduce exogenous antigens into genetically engineered mouse lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors.

PMID: 21251614 [PubMed - indexed for MEDLINE]

Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase.

PubMed - Tue, 10/24/2017 - 11:31
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Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase.

Nat Protoc. 2009;4(7):1064-72

Authors: DuPage M, Dooley AL, Jacks T

Abstract
The development of animal models of lung cancer is critical to our understanding and treatment of the human disease. Conditional mouse models provide new opportunities for testing novel chemopreventatives, therapeutics and screening methods that are not possible with cultured cell lines or xenograft models. This protocol describes how to initiate tumors in two conditional genetic models of human non-small cell lung cancer (NSCLC) using the activation of oncogenic K-ras alone or in combination with the loss of function of p53. We discuss methods for sporadic expression of Cre in the lungs through engineered adenovirus or lentivirus, and provide a detailed protocol for the administration of the virus by intranasal inhalation or intratracheal intubation. The protocol requires 1-5 min per mouse with an additional 30-45 min to set-up and allow for the recovery of mice from anesthesia. Mice may be analyzed for tumor formation and progression starting 2-3 weeks after infection.

PMID: 19561589 [PubMed - indexed for MEDLINE]

Regulated expression of a tumor-associated antigen reveals multiple levels of T-cell tolerance in a mouse model of lung cancer.

PubMed - Tue, 10/24/2017 - 11:31
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Regulated expression of a tumor-associated antigen reveals multiple levels of T-cell tolerance in a mouse model of lung cancer.

Cancer Res. 2008 Nov 15;68(22):9459-68

Authors: Cheung AF, Dupage MJ, Dong HK, Chen J, Jacks T

Abstract
Maximizing the potential of cancer immunotherapy requires model systems that closely recapitulate human disease to study T-cell responses to tumor antigens and to test immunotherapeutic strategies. We have created a new system that is compatible with Cre-LoxP-regulatable mouse cancer models in which the SIY antigen is specifically overexpressed in tumors, mimicking clinically relevant TAAs. To show the utility of this system, we have characterized SIY-reactive T cells in the context of lung adenocarcinoma, revealing multiple levels of antigen-specific T-cell tolerance that serve to limit an effective antitumor response. Thymic deletion reduced the number of SIY-reactive T cells present in the animals. When potentially self-reactive T cells in the periphery were activated, they were efficiently eliminated. Inhibition of apoptosis resulted in more persistent self-reactive T cells, but these cells became anergic to antigen stimulation. Finally, in the presence of tumors overexpressing SIY, SIY-specific T cells required a higher level of costimulation to achieve functional activation. This system represents a valuable tool in which to explore sources contributing to T-cell tolerance of cancer and to test therapies aimed at overcoming this tolerance.

PMID: 19010921 [PubMed - indexed for MEDLINE]