Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways

Laxmanan, Sreenivas; Robertson, Stuart W.; Wang, Enfeng; Lau, Julie S.; Briscoe, David M.; Mukhopadhyay, Debabrata

doi:10.1016/j.bbrc.2005.06.065

Cited by 87 publications

(70 citation statements)

References 22 publications

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“…However, in our in vitro incubation system of human leukocytes, we cannot rule out the possibility that coexisted iMC might have inhibited the maturation of DC during overnight incubation time. By using in vitro culture system of murine cells, Dikov et al [17] and Laxmanan et al [33] reported the direct impairment of DC function by VEGF is mediated primarily by VEGFR1/Flt-1. Dikov reported that VEGF acted on early stage of DC differentiation but not later phase of maturation.…”

Section: Discussionmentioning

confidence: 99%

The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients

Osada

Chong

Tansik

et al. 2008

Cancer Immunol Immunother

277

177

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Impairment of dendritic cells (DC), the most effective activators of anti-cancer immune responses, is one mechanism for defective anti-tumor immunity, but the causes of DC impairment are incompletely understood. We evaluated the association of impaired DC differentiation with angiogenesis-associated molecules D-dimer, vascular endothelial growth factor (VEGF), urokinase plasminogen activator and plasminogen activator inhibitor (PAI-1) in peripheral blood from 41 patients with lung, breast, and colorectal carcinoma. Subsequently, we studied the effect of administration of the anti-VEGF antibody (bevacizumab) on DC maturation and function in vivo. Compared with healthy volunteers, cancer patients had a bias towards the immunoregulatory DC2, had deficits in DC maturation after overnight in vitro culture, and had a significant increase in immature myeloid cell progenitors of DC (0.50 +/− 0.31% vs. 0.32 +/− 0.16%, respectively, p=0.011). A positive correlation was found between the percentage of DC2 and PAI-1 (R=0.50) and between immature myeloid cells and VEGF (R=0.52). Bevacizumab administration to cancer patients was associated with a decrease in the accumulation of immature progenitor cells (0.39 +/− 0.30 % vs. 0.27 +/− 0.24 %, p=0.012) and induced a modest increase in the DC population in peripheral blood (0.47 +/− 0.23 % vs. 0.53 +/− 0.30 %). Moreover, anti-VEGF antibody treatment enhanced allo-stimulatory capacity of DC and T cell proliferation against recall antigens. These data suggest that DC differentiation is negatively associated with VEGF levels and may be one explanation for impaired anti-cancer immunity, especially in patients with advanced malignancies.

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Section: Discussionmentioning

confidence: 99%

The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients

Osada

Chong

Tansik

et al. 2008

Cancer Immunol Immunother

277

177

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“…Furthermore, murine models have indicated that VEGF inhibition may be a means of overcoming immune resistance 42,43 and, thus, may enhance the IL-2 antitumor effect that potentially is increased by LEN.…”

Section: Discussionmentioning

confidence: 99%

Phase II study of lenalidomide in patients with metastatic renal cell carcinoma

Choueiri

Dreicer

Rini

et al. 2006

Cancer

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BACKGROUND. Lenalidomide (LEN) is a structural and functional analogue of thalidomide that has demonstrated enhanced immunomodulatory properties and a more favorable toxicity profile. A Phase II, open‐label study of LEN in patients with metastatic renal cell carcinoma (RCC) was conducted to determine its safety and clinical activity. METHODS. Patients with metastatic RCC received LEN orally at a dose of 25 mg daily for the first 21 days of a 28‐day cycle. The primary endpoint was the objective response rate. Time to treatment failure, safety, and survival were secondary endpoints. RESULTS. In total, 28 patients participated in the trial and were included in the current analysis. Three of 28 patients (11%) demonstrated partial responses and continued to be progression‐free for >15 months. Eleven patients (39%) had stable disease that lasted >3 months, including 8 patients who had tumor shrinkage. In total, 6 patients (21%) remained on the trial, and 5 additional patients continued to be followed for survival. The median follow‐up for those 11 patients was 13.5 months (range, 8.3–17.0 months). The median survival had not been reached at the time of the current report. Serious adverse events included fatigue (11%), skin toxicity (11%), and neutropenia (36%). CONCLUSIONS. LEN demonstrated an antitumor effect in metastatic RCC, as evidenced by durable partial responses. LEN toxicities were manageable. Further studies will be required to assess the overall activity of LEN in patients with metastatic RCC. Cancer 2006. © 2006 American Cancer Society.

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“…In the presence of VEGF during culture, DC from wild-type mice displayed an inhibition of antigen presentation capacity, which was not observed for DC from Id1 −/− mice under the same experimental settings. Furthermore, addition of neutralizing anti-Flt-1 antibody abrogated the inhibitory effect of VEGF on wild-type DCs (Laxmanan, et al 2005). …”

Section: Cytokines/chemokinesmentioning

confidence: 99%

Dendritic Cells and Tumor Microenvironment: A Dangerous Liaison

Fricke

Gabrilovich

2006

Immunological Investigations

145

112

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The fact that the immune response to cancer is compromised has been convincingly demonstrated in murine tumor models as well as in cancer patients. The unresponsiveness of the host immune system is one of the major mechanisms of tumor escape as well as an important factor that limits the success of cancer immunotherapy. Inadequate function of professional antigen presenting cells dendritic cells (DC) in cancer is one of the major elements of compromised anti-tumor immune response. Despite substantial progress in recent years, the mechanism of inadequate DC function in cancer still remains unclear. The tumor microenvironment has emerged as an important component contributing to DC malfunction. In this review we will discuss the potential role of tumor microenvironment in DC dysfunction.

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Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways

Cited by 87 publications

References 22 publications

The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients

The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients

Phase II study of lenalidomide in patients with metastatic renal cell carcinoma

Dendritic Cells and Tumor Microenvironment: A Dangerous Liaison

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