CD47 Signaling Regulates the Immunosuppressive Activity of VEGF in T Cells

Kaur, Sukhbir; Chang, Tiffany; Singh, Satya P.; Lim, Li Hong Idris; Mannan, Poonam; Garfield, Susan H.; Pendrak, Michael L.; Soto-Pantoja, David R.; Rosenberg, Avi Z.; Jin, Shelly; Roberts, D. A.

doi:10.4049/jimmunol.1303116

Cited by 98 publications

(73 citation statements)

References 45 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Suppression of CD47 in effector T cells causes an autonomous increase in granzyme B expression that can mediate target tumor cell death. Enhanced T cell activation following CD47 blockade is consistent with the well-established inhibitory CD47 signaling pathways activated by TSP1 binding to CD47 on T cells (9, 12, 16, 18, 20, 41). …”

Section: Discussionsupporting

confidence: 77%

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

et al. 2014

Self Cite

View full text Add to dashboard Cite

While significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here we report that CD47 blockade directly enhances tumor immunosurveillance by CD8+ T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8+ T cells restored combinatorial efficacy. Further, ablation of CD8+ T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8+ CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8+ T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8+ T cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8+ cytotoxic T cells, with the potential to increase curative responses.

show abstract

Section: Discussionsupporting

confidence: 77%

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Indeed, MAPK1 is the most significantly identified upstream regulator in unique genes with altered DNA methylation in lupus patients with renal involvement ( P = 9.58 × 10 −8 ) (Table 2). Genes hypermethylated only in lupus patients with renal involvement include CD47 which has been recently shown to regulate the immunosuppressive function of VEGF in T cells [21], and CD247 which encodes the T cell receptor zeta chain and is known to be down-regulated in lupus T cells [22]. …”

Section: Discussionmentioning

confidence: 99%

Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells

Coit

Renauer

Jeffries

et al. 2015

Journal of Autoimmunity

116

View full text Add to dashboard Cite

Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits the ERK signaling pathway, were among the most hypomethylated. Independent of disease activity, renal involvement is characterized by more robust demethylation in interferon regulated genes differentially methylated in both sets of lupus patients with and without renal involvement (fold change 1.4, P = 0.0014). The type-I interferon master regulator gene IRF7 is only hypomethylated in lupus patients with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, IRF7, ISG15, ISG20, ITGAX, and PARP12 (P = 1.78 × 10−6). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for stratifying lupus patients for a history of renal involvement (P = 0.0029). Our data identified novel epigenetic susceptibility loci that are differentially methylated with renal involvement in lupus. These loci will help better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvement in lupus.

show abstract

“…It has been reported that VEGF secreted by mouse tumor cells prevented dendritic cells from maturing, thereby hampering tumor antigen presentation (Gabrilovich et al 1996). VEGF expression is present in cytotoxic T cells, and it has been shown that increased expression of VEGF and VEGFR2 suppressed the activity of the T-cell receptor CD47 and cytotoxic T cell function (Kaur et al 2014). Altered VEGF signaling may also suppress the function of dendritic cells and indirectly inhibit T-cell infiltration of tumor tissue.…”

Section: Vegf Signaling Bone Metastasis and Nichesmentioning

confidence: 99%

Regulation of vascular endothelial growth factor in prostate cancer

Brot¹,

Ntekim²,

Cardenas³

et al. 2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

Prostate cancer (PCa) is the most common malignancy affecting men in the western world. Although radical prostatectomy and radiation therapy can successfully treat PCa in the majority of patients, up to w30% will experience local recurrence or metastatic disease. Prostate carcinogenesis and progression is typically an androgen-dependent process. For this reason, therapies for recurrent PCa target androgen biosynthesis and androgen receptor function. Such androgen deprivation therapies (ADT) are effective initially, but the duration of response is typically %24 months. Although ADT and taxane-based chemotherapy have delivered survival benefits, metastatic PCa remains incurable. Therefore, it is essential to establish the cellular and molecular mechanisms that enable localized PCas to invade and disseminate. It has long been accepted that metastases require angiogenesis. In the present review, we examine the essential role for angiogenesis in PCa metastases, and we focus in particular on the current understanding of the regulation of vascular endothelial growth factor (VEGF) in localized and metastatic PCa. We highlight recent advances in understanding the role of VEGF in regulating the interaction of cancer cells with tumor-associated immune cells during the metastatic process of PCa. We summarize the established mechanisms of transcriptional and post-transcriptional regulation of VEGF in PCa cells and outline the molecular insights obtained from preclinical animal models of PCa. Finally, we summarize the current state of anti-angiogenesis therapies for PCa and consider how existing therapies impact VEGF signaling.

show abstract

CD47 Signaling Regulates the Immunosuppressive Activity of VEGF in T Cells

Cited by 98 publications

References 45 publications

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells

Regulation of vascular endothelial growth factor in prostate cancer

Contact Info

Product

Resources

About