Effects of definitive chemoradiation on circulating immunologic angiogenic cytokines in head and neck cancer patients

Abstract

BackgroundPreclinical studies suggest a synergistic effect between radiation, immunotherapy and anti-angiogenic therapy, although the mechanisms are unclear. Angiogenic cytokines are known to affect the immune system, and their levels may be associated with response to immunotherapy. Here, we assess changes in circulating VEGF, as well as angiogenic cytokines angiopoietin-1 and -2 (Ang1, Ang2), and placental growth factor (PLGF) that occur during definitive chemo-radiotherapy in HNSCC patients.MethodsWe prospectively collected blood samples from patients receiving definitive radiation with or without chemotherapy. Serum Ang1, Ang2, VEGF, and PLGF were measured via cytokine assays.ResultsThe majority of patients had advanced stage, node positive HPV-associated oropharyngeal cancer, and received radiation to a median dose of 70 Gy with concurrent cisplatin. Over the course of treatment, serum VEGF and Ang1 levels decreased in 20/24 (84 %, p < 0.0001) and 21/24 (88 %, p < 0.0001) patients, respectively, and Ang2 and PLGF levels increased in 20/24 (83 %, p < 0.0001) patients.ConclusionsWe find significant changes in angiogenic cytokines in the majority of HNSCC patients over the course of chemoradiation. Decreases in VEGF caused by radiation may represent one mechanism of potential synergy with immunotherapy. Increases in Ang2 and PLGF are interesting given their link to tumor associated angiogenesis and poor prognosis. Additional studies are needed to explore synergies between anti-angiogenic treatments, immunotherapy, and chemoradiation in HNSCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0138-9) contains supplementary material, which is available to authorized users.

Combined modality radiation therapy promotes tolerogenic myeloid cell populations and STAT3-related gene expression in head and neck cancer patients

“…VEGF plays key immunomodulatory roles in cancer patients by inhibiting maturation of dendritic cells and promoting accumulation of regulatory T cells and MDSC [ 38 ]. In contrast to our observation, Sridharan et al recently reported decrease in VEGF level in HNSCC patients who received radiation to a dose of 70Gy concurrently with cisplatin [ 39 ]. The discrepancy may result from the greater number of low grade cancers included in this analysis, which also found the inverse correlation between tumor staging and the level of VEGF, with the highest VEGF levels in the T1-tumor stage patients.…”

Combined radiotherapy and immunotherapy in urothelial bladder cancer: harnessing the full potential of the anti-tumor immune response

“…The adverse effects (AEs) associated with ICIs use (irAEs) and their management are well documented [54]. RT-related AEs are thought to be in part related to the immune system response, mostly through its effects on pro-inflammatory and fibrogenic cytokines [55]. There are concerns that the combination of RT and immunotherapy could lead to a cumulative toxicity profile.…”

Antiangiogenic agents in head and neck squamous cell carcinoma: Tired of going solo

“…This combination may be an important strategy in SCCHN. Data from our institution indicate that chemoradiation for locally advanced SCCHN significantly impacts circulating angiogenic cytokines, which are known to have immunomodulatory effects, and we observed a decrease in VEGF and Ang‐1 and an increase in Ang‐2 and placental growth factor after chemoradiation . Angiogenesis inhibitors can modulate the tumor microenvironment to improve tumor blood flow and oxygenation, leading to enhanced radiosensitivity .…”

“…Data from our institution indicate that chemoradiation for locally advanced SCCHN significantly impacts circulating angiogenic cytokines, which are known to have immunomodulatory effects, and we observed a decrease in VEGF and Ang-1 and an increase in Ang-2 and placental growth factor after chemoradiation. 22 Angiogenesis inhibitors can modulate the tumor microenvironment to improve tumor blood flow and oxygenation, leading to enhanced radiosensitivity. 23 Taken together, these findings suggest that the combination of antiangiogenic agents with immunotherapy and radiation may be a promising approach, particularly for patients with high-risk, locally advanced SCCHN, for whom there is a significant need to improve cure rates.…”