Inhibitory costimulation and anti-tumor immunity

Martín‐Orozco, Natalia; Dong, Chen

doi:10.1016/j.semcancer.2007.06.003

Cited by 27 publications

(24 citation statements)

References 116 publications

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“…Moreover, human BTN2A1 has been shown to modulate immature dendritic cells (DC) by binding to Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) [41], and Btnl1 has been recently found to regulate interactions with intraepithelial γδT lymphocytes in the murine small intestine by suppressing pro-inflammatory mediators of the NFκB pathway, such as IL-6, IL-15, CXCL1, and CCL4 [42]. In addition, many members of the B7-homolog (B7-H) family, such as PD-1 and CTLA-4, are expressed on tumour cells in various cancers, where they can be exploited by the cancerous cells to escape from immune destruction and impede B7 ongoing immune processes [43,44]. The presence of the deletion and the subsequent absence or reduced expression of the encoded proteins would allow a stronger response against tumour cells, implying that the BTNL8_BTNL3-del allele could act as a positive modulator of anti-tumour immunity.…”

Section: Discussionmentioning

confidence: 99%

A common 56-kilobase deletion in a primate-specific segmental duplication creates a novel butyrophilin-like protein

et al. 2013

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BackgroundThe Butyrophilin-like (BTNL) proteins are likely to play an important role in inflammation and immune response. Like the B7 protein family, many human and murine BTNL members have been shown to control T lymphocytes response, and polymorphisms in human BTNL2 have been linked to several inflammatory diseases, such as pulmonary sarcoidosis, inflammatory bowel disease and neonatal lupus.ResultsIn this study we provide a comprehensive population, genomic and transcriptomic analysis of a 56-kb deletion copy number variant (CNV), located within two segmental duplications of two genes belonging to the BTNL family, namely BTNL8 and BTNL3. We confirm the presence of a novel BTNL8*3 fusion-protein product, and show an influence of the deletion variant on the expression level of several genes involved in immune function, including BTNL9, another member of the same family. Moreover, by genotyping HapMap and human diversity panel (HGDP) samples, we demonstrate a clear difference in the stratification of the BTNL8_BTNL3-del allele frequency between major continental human populations.ConclusionDespite tremendous progress in the field of structural variation, rather few CNVs have been functionally characterized so far. Here, we show clear functional consequences of a new deletion CNV (BTNL8_BTNL3-del) with potentially important implication in the human immune system and in inflammatory and proliferative disorders. In addition, the marked population differences found of BTNL8_BTNL3-del frequencies suggest that this deletion CNV might have evolved under positive selection due to environmental conditions in some populations, with potential phenotypic consequences.

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Section: Discussionmentioning

confidence: 99%

A common 56-kilobase deletion in a primate-specific segmental duplication creates a novel butyrophilin-like protein

et al. 2013

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“…The extended B7 family also include ICOS ligand (ICOSL, also known as B7h, ICOS-L, B7RP-1, and B7-H2), B7-H1(also known as PD-L1, B7-H, CD274), B7-H2 (also known as PD-L2 and B7-DC), B7-H3 (also known as CD276 and B7RP-2), and B7-H4 (also known as VTCN1, B7X, and B7S1). They play variable roles in maintaining the intricate cellular network of the tumor immune suppressive microenvironment [8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract

Chen

Liu

et al. 2011

Immunol Res

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Tumorigenesis can induce adaptive T-cell-mediated immune responses against malignant cells. Such cellular immune responses are actively suppressed by cancer cells via mechanisms of immune tolerance. We studied T-cell responses against tumor growth by examining tumor-infiltrating lymphocytes (TILs) in upper gastrointestinal (GI) cancers. The number of T-bet(+) TILs correlates with better survival of esophageal cancer patients. Using well-defined mouse models, we have further shown that T-bet and Eomes are both required for the adaptive anti-tumor immunity by regulating T-cell trafficking into the tumor tissue and their effector functions inside the tumor microenvironment. In order to gain further insight into the tumor immune microenvironment in the upper GI cancer, we have also studied expression levels of co-inhibitory molecules such as B7-H1/PD-L1 and B7-H4 in tissue specimens of esophageal and gastric cancers. These inhibitory B7 molecules were expressed at high but variable levels by cancer cells. The overexpression of these molecules correlates with poor clinicopathological parameters and shorter patient survival time. The number of CD3(+) and CD8(+) TILs correlates inversely with expression levels of B7-H4 in samples from esophageal cancer, supporting a role of active immune suppression by inhibitory B7 molecules in the tumor microenvironment. In addition, TILs show functional exhaustion and express high levels of PD-1 and Tim-3. We propose that metabolic competition mediated by phosphatidylinositol 3-kinases (PI3Ks) characterizes the immune suppression within cancer tissues. Future tumor vaccine design should combine blockade of B7 inhibitory molecules and enhancement of T-bet and Eomes levels within the tumor microenvironment.

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“…T cell activation is regulated simultaneously by positive and negative signals, in part but importantly via the interaction of costimulatory molecules between receptors on T cells and their ligands on APCs (1)(2)(3). In addition to CD28 and ICOS, which provide positive costimulation to enhance T cell activation, numerous inhibitory ligands or receptors have been identified that regulate immune tolerance and/or the magnitude of T cell immune responses.…”

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A Butyrophilin Family Member Critically Inhibits T Cell Activation

Yamazaki¹,

Goya

Graf

et al. 2010

The Journal of Immunology

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The costimulatory molecules in the B7-CD28 families are important in the regulation of T cell activation and tolerance. The butyrophilin family of proteins shares sequence and structure homology with B7 family molecules; however, the function of the butyrophilin family in the immune system has not been defined. In this study, we performed an analysis on multiple butyrophilin molecules and found that butyrophilin-like (BTNL)1 molecule functions to dampen T cell activation. BTNL1 mRNA was broadly expressed, but its protein was only found in APCs and not T cells. The putative receptor for BTNL1 was found on activated T cells and APCs. Also, recombinant BTNL1 molecule inhibited T cell proliferation by arresting cell cycle progression. The administration of neutralizing Abs against BTNL1 provoked enhanced T cell activation and exacerbated disease in autoimmune and asthma mouse models. Therefore, BTNL1 is a critical inhibitory molecule for T cell activation and immune diseases.

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Inhibitory costimulation and anti-tumor immunity

Cited by 27 publications

References 116 publications

A common 56-kilobase deletion in a primate-specific segmental duplication creates a novel butyrophilin-like protein

A common 56-kilobase deletion in a primate-specific segmental duplication creates a novel butyrophilin-like protein

T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract

A Butyrophilin Family Member Critically Inhibits T Cell Activation

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