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Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.

ABSTRACT: The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1beta, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages) while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1beta and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients.

SUBMITTER: Roland CL

PROVIDER: S-EPMC2766251 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.

Roland Christina L CL Lynn Kristi D KD Toombs Jason E JE Dineen Sean P SP Udugamasooriya D Gomika DG Brekken Rolf A RA

PloS one 20091103 11

The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tum ...[more]

PMID: 19888452

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Project description:Objective This study aimed to investigate the diagnostic value and underlying mechanisms of sialic acid-binding Ig-like lectin 9 (SIGLEC9) in gliomas. Patients and Methods The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were used to analyze the association of SIGLEC9 expression levels with tumor stages and survival probability. Immunohistochemical staining of SIGLEC9 and survival analysis were performed in 177 glioma patients. Furthermore, related mechanisms were discovered about SIGLEC9 in glioma tumorigenesis, and we reveal how SIGLEC9 functions in macrophages through single-cell analysis. Results TCGA and CGGA databases indicated that patients with high SIGLEC9 expression manifested a significantly shorter survival probability than those with low SIGLEC9 expression. SIGLEC9 was upregulated significantly in malignant pathological types, such as grade III, grade IV, mesenchymal subtype, and isocitrate dehydrogenase wild-type gliomas. The immunohistochemical staining of tissue sections from 177 glioma patients showed that high-SIGLEC9-expression patients manifested a significantly shorter survival probability than low-SIGLEC9-expression patients with age ≧60 years, grade IV, glioblastoma multiforme, alpha thalassemia/intellectual disability syndrome X-linked loss, and without radiotherapy or chemotherapy. Furthermore, the SIGLEC9 expression level was positively correlated with myeloid-derived suppressor cell infiltration and neutrophil activation. The SIGLEC9 expression was also positively correlated with major immune checkpoints, such as LAIR1, HAVCR2, CD86, and LGALS9. Through single-cell analysis, we found that the SIGLEC9 gene is related to the ability of macrophages to process antigens and the proliferation of macrophages. Conclusion These findings suggested that SIGLEC9 is a diagnostic marker of poor outcomes in glioma and might serve as a potential immunotherapy target for glioma patients in the future.

Project description:The efficacy of programmed cell death‑ligand 1 (PD‑L1)/programmed cell death protein 1 (PD‑1) blockade therapy has been demonstrated but is limited in patients with PD‑L1low or immune desert tumors. This limitation can be overcome by combination therapies that include anti‑vascular endothelial growth factor (VEGF) therapy. Such combinations have been investigated in clinical trials for a number of cancer types; however, evidence on the mechanisms underlying their effects in these types of patients is still not sufficient. Therefore, the present study investigated the efficacy and effects on CD8+ T cell and C‑X‑C motif chemokine receptor 3 (CXCR3) ligand expression in tumors by combining anti‑PD‑L1 and anti‑VEGF antibodies using an OV2944‑HM‑1 mouse model with PD‑L1low and immune desert‑like phenotypes. Although the model exhibited anti‑PD‑L1 insensitivity, anti‑PD‑L1 antibody treatment combined with anti‑VEGF antibody inhibited tumor growth compared with anti‑VEGF monotherapy, which itself inhibited tumor growth compared with the control treatment on Day 25. In combination‑treated mice, a higher percentage of CD8+ T cells and higher levels of CXCR3 ligands were observed in tumor tissues compared with those in the anti‑VEGF antibody treatment group, which was not significantly different from control treatment on Day 8. The increase in the intratumoral percentage of CD8+ T cells following the combination treatment was reversed by CXCR3 blocking to the same level as the control. In an anti‑PD‑L1 insensitive model with PD‑L1low and immune desert‑like phenotypes, although anti‑PD‑L1 antibody alone was not effective, anti‑PD‑L1 antibody in combination with anti‑VEGF antibody exhibited antitumor combination efficacy with an increase of CD8+ T cell infiltration, which was suggested to be dependent on the increase of intratumoral CXCR3 ligands. This mechanism could explain the efficacy of anti‑PD‑L1 antibody and anti‑VEGF antibody combination therapy in the clinical setting.

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Dataset Information

Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.

Publications

Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.

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