T cell exclusion, immune privilege, and the tumor microenvironment

Joyce, Johanna A.; Fearon, Douglas T.

doi:10.1126/science.aaa6204

Cited by 1,735 publications

(1,337 citation statements)

References 78 publications

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“…13 Accumulating data suggest that a critical determinant of therapeutic success is to overcome tumor-dependent immunosuppression. [14][15][16][17] Tumor-infiltrating T cells not only encounter a hostile microenvironment characterized by low oxygen and glucose conditions 18,19 but also active suppression by cells like regulatory T cells, tumor-associated macrophages or myeloid-derived suppressor cells (MDSC). 20,21 MDSC are a heterogeneous population of immature myeloid cells inhibiting antitumor reactivity of T and NK cells.…”

Section: Introductionmentioning

confidence: 99%

Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening

et al. 2016

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Tumors are infiltrated by cells of the immune system that interact through complex regulatory networks. Although tumor-specific CD8 C T cells can be found in peripheral blood and tumor samples from cancer patients, their function is inhibited by immunosuppressive cells such as regulatory T cells, tumorassociated macrophages, and myeloid-derived suppressor cells (MDSC). Recent clinical successes have demonstrated that alleviating immunosuppression and T cell exhaustion translates into long-term clinical benefits. Although tremendous progress has been achieved, tools that afford unbiased approaches and screenings to uncover new potential inhibitors or gene targets are lacking. In this study, we describe a system based on immortalized progenitors that allows straightforward investigation of myeloid cells. We show that bone marrow progenitors immortalized through the transduction of NUP98-HOXB4 transgene can be differentiated into CD11b C Gr-1 C MDSC that express Arginase-1 and PD-L1, produce reactive oxygen and nitrogen species, and suppress T cell function in vitro. To uncover chemical probes that interfere with MDSC biology, we performed a chemical phenotypic screening and identified 3-deazaneplanocin A as a novel modulator of MDSC functions. We characterized and compared the effect of 3-deazaneplanocin-A and all-trans retinoic acid, a well-known modulator of MDSC activity, on the expression of effector molecules and immunosuppressive functions of MDSC. Altogether, this proof-ofprinciple opens new possibilities for the identification of drugs targeting myeloid cells with immunosuppressive activities.

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Section: Introductionmentioning

confidence: 99%

Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening

et al. 2016

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“…Kanserlerin immün korunaklı yapıları mevcuttur ve bu sayede immün sistem tarafından tanınmazlar (14). Melanoma hastalarının bir kısmında vitiligo geliştiği gözlemlenmiştir.…”

Section: Melanomda İmmünoterapiunclassified

“…Melanoma hastalarının bir kısmında vitiligo geliştiği gözlemlenmiştir. Özellikle metastatik hastalığa sahip bazı hastalarda vitiligonun uzun süreli sağkalım ile ilişkili olduğu gözlenmiştir (14). İmmünoterapi almakta olan hastaların bir kısmında da vitiligo geliştiği gözlenmiştir.…”

Section: Melanomda İmmünoterapiunclassified

Current Treatment Modalities in Advanced Melanoma

Güngör¹,

Akay²

2016

tdd

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Melanom deri kanserlerine bağlı ölümlerin en önemli sebebidir ve son yıllarda insidansında giderek artış gözlenmektedir. Erken tanıya yönelik tüm çabalara rağmen, metastatik melanom halen kötü prognoza sahip bir neoplazm olup tedavi eden doktorlar için sorun olmaya devam etmektedir. Son yıllarda patofizyolojinin ve immün sistemin tümör kontrolü üzerindeki rolünün daha iyi anlaşılması hedefe yönelik tedavilerin ve çeşitli immünoterapi ajanlarının geliştirilmesine imkan vermiştir. İmmün kontrol noktası inhibitör antikorları ve hedefe yönelik tedaviler metastatik melanomlu hastalarda klinik cevabı dramatik olarak artırmıştır. Bu derlemede metastatik melanom tedavisinde yeni geliştirilen ve onaylanan tedavilerin sonuçları anlatılmıştır. Anahtar kelimeler: Melanom, metastatik, immünoterapi, hedefe yönelik tedavi, tedavi, yöntemler Hilayda KarakökGüngör, Bengü Nisa Akay İlerlemiş Melanomada Kullanılan Güncel Tedavi Yöntemleri Current Treatment Modalities in Advanced Melanoma Öz AbstractMelanoma contributes the majority of skin cancer related deaths and shows an increasing incidence in the past years. Despite all efforts of early diagnosis, metastatic melanoma still has a poor prognosis and remains a challenge for physicians to treat. In recent years, improved knowledge of the pathophysiology and a better understanding of the role of the immune system in tumour control have led to the development and approval of several immunotherapies and targeted therapies. The introduction and Food and Drug Administration approval of immune checkpoint inhibitor antibodies and targeted therapies has dramatically improved the clinical outcomes for patients with advanced melanoma. In this review, results of these recently developed and approved therapies for metastatic melanoma were presented.

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“…These include checkpoints or roadblocks (cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1) and its ligand PD-L1) for T cell activation and function [24][25][26], regulatory T cells, other immunosuppressive cells and inhibitory cytokines [27][28][29][30][31][32][33]. To enhance antitumor immunity, it is necessary to remove these roadblocks so that T cells can be fully activated and functional for the eradication of cancer cells.…”

Section: Introductionmentioning

confidence: 99%