Costimulatory and coinhibitory receptors in anti‐tumor immunity

Driessens, Grégory; Kline, Justin; Gajewski, Thomas F.

doi:10.1111/j.1600-065x.2009.00771.x

Cited by 249 publications

(213 citation statements)

References 210 publications

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“…The expression and functional relevance of members of the B7 costimulatory family in tumor lesions of distinct histology have been frequently reported (13,17). Limited data are available for melanoma and in particular, the expression and significance of B7-H3 and B7-H4 molecules have not yet been analyzed in detail.…”

Section: Discussionmentioning

confidence: 99%

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B7-H4 Expression in Human Melanoma: Its Association with Patients' Survival and Antitumor Immune Response

Quandt

Fiedler

Boettcher

et al. 2011

Clinical Cancer Research

129

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Purpose: Cancers have developed a number of strategies to escape immune responses including the differential expression of costimulatory molecules of the B7 family. B7-H3 and B7-H4 have recently been described in different tumor entities but the relevance for melanoma has not yet been studied so far.Experimental Design: Using immunohistochemistry, B7-H3 and B7-H4 expression was studied on 29 melanoma lesions. Survival curves and log-rank tests were used to test the association of protein expression with survival. Cell lines were evaluated for B7-H3 and B7-H4 expression by PCR and flow cytometry. Functional T-cell-tumor coculture assays were carried out with in vitro generated tumor transfectants.Results: B7-H3 and B7-H4 expression was detected in primary tumor lesions (29 of 29 and 28 of 29) and in metastases (28 of 29 and 26 of 29). The numbers of CD68 þ macrophages were significantly lower in patients with low B7-H4 expression, whereas CD8 þ T-cell infiltrates were independent of expression levels.Furthermore, a survival benefit for patients with B7-H4 low expressing melanoma was found, whereas B7-H3 was not associated with any clinical parameter. All 23 melanoma cell lines analyzed expressed B7-H3 and B7-H4 mRNA and protein, but B7-H4 was restricted to intracellular compartments. On silencing of B7-H3 by specific shRNA tumor-associated antigen-specific T cell responses were unaltered. Overexpression of B7-H4 on melanoma cells did not alter the cytotoxicity of different CD8 þ effector cells, but drastically inhibited cytokine production. Conclusions: Our study provides for the first time evidence of B7-H4 expression on melanoma cells as a mechanism controlling tumor immunity which is associated with patients' survival. Clin Cancer Res; 17(10); 3100-11. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

“…11). Even though many studies have shown an inhibitory role for B7-H4 (13) in the setting of progressive renal disease, a costimulatory activity of B7-H4 has also been proposed (14). So far, the receptor for B7-H4 has not been identified (12).…”

Section: Introductionmentioning

confidence: 99%

B7-H4 Expression in Human Melanoma: Its Association with Patients' Survival and Antitumor Immune Response

Quandt

Fiedler

Boettcher

et al. 2011

Clinical Cancer Research

129

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“…It has been well-documented in the recent decade that various tumors were able to exert immunogenic properties inducing strong anti-tumor immune reactions, in which T cells were shown to play a key role [1][2][3]. Numerous publications revealed a strong correlation between an infiltration of tumor lesions in cancer patients with T lymphocytes and better clinical outcome [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

Umansky

Sevko

2012

Cancer Microenvironment

118

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Tumor progression has been demonstrated to be supported by chronic inflammatory conditions developed in the tumor microenvironment and characterized by the longterm secretion of various inflammatory soluble factors (including cytokines, chemokines, growth factors, reactive oxygen and nitrogen species, prostaglandins etc.) and strong leukocyte infiltration. Among leukocytes infiltrating tumors, myeloid-derived suppressor cells (MDSCs) represent one of the most important players mediating immunosuppression. These cells may not only strongly inhibit an anti-tumor immune reactions mediated by T cells but also directly stimulate tumorigenesis, tumor growth and metastasis by enhancing neoangiogenesis and creating a suitable environment for the metastatic formation. This review provides an overview of interactions between MDSCs and tumor cells leading to MDSC generation, activation and migration to the tumor site, where they can strongly enhance tumor progression. Better understanding of the MDSC-tumor interplay is critical for the development of new strategies of tumor immunotherapy.

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“…However, multiple regulatory mechanisms that blunt T cell function within the tumor microenvironment arise in tumors (27). Programmed death ligand 1 (PD-L1), an inhibitory molecule frequently upregulated on tumor cells, is one of the major immunological checkpoints contributing to tumor-immune escape (28) through the inhibition of T cell activation and promotion of apoptosis of DCs (29) and CD8 + T cells (30). In several clinical trials, blockade of programmed death-1 (PD-1) or PD-L1 resulted in enhanced T cell function and improved immune-mediated tumor control (31).…”

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confidence: 99%

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

Iraolagoitia

Spallanzani

Torres

et al. 2016

The Journal of Immunology

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Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8+ T cells, leading to reduced memory responses. After challenge with MC57 cells transduced to express the model Ag SIY (MC57.SIY), NK cell–depleted mice exhibited a significantly higher frequency of SIY-specific CD8+ T cells, with enhanced IFN-γ production and cytotoxic capability. Depletion of NK cells resulted in a CD8+ T cell population skewed toward an effector memory T phenotype that was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Dendritic cells (DCs) from NK cell–depleted tumor-bearing mice exhibited a more mature phenotype. Interestingly, tumor-infiltrating and tumor-draining lymph node NK cells displayed an upregulated expression of the inhibitory molecule programmed death ligand 1 that, through interaction with programmed death-1 expressed on DCs, limited DC activation, explaining their reduced ability to induce tumor-specific CD8+ T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on antitumor immunity, a finding with implications for immunotherapy in the clinic.

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Costimulatory and coinhibitory receptors in anti‐tumor immunity

Cited by 249 publications

References 210 publications

B7-H4 Expression in Human Melanoma: Its Association with Patients' Survival and Antitumor Immune Response

B7-H4 Expression in Human Melanoma: Its Association with Patients' Survival and Antitumor Immune Response

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

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