B7-H4(B7x)-mediated cross-talk between glioma-initiating cells and macrophages via the IL6/JAK/STAT3 pathway lead to poor prognosis in glioma patients

Yu Yao, Hongxing Ye, Zengxin Qi, Lianjie Mo, Qi Yue, Aparajita Baral, Dave S.B. Hoon, Juan Carlos Vera, John D. Heiss, Clark C. Chen, Wei Hua, Jianmin Zhang, Kunlin Jin, Yin Wang, Ying Mao, Xingxing Zang, Liangfu Zhou

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Abstract

Purpose: The objective of this study was to evaluate clinical significance and immunosuppressive mechanisms of B7-H4 (B7x/B7S1), a B7 family member, in glioma. Experimental Design: B7-H4 levels in glioma tissue/cerebral spinal fluid (CSF) were compared between different grades of glioma patients. Survival data were analyzed with Kaplan-Meier to determine the prognostic value of B7-H4. Cytokines from CD133 cells to stimulate the expression of B7-H4 on human macrophages (Mjs) were investigated by FACS, neutralizing antibodies, and Transwell chemotaxis assay. shRNA, reporter vector, and chromatin immunoprecipitation were used to determine the binding of STAT3 to the B7-H4 promoter. The function of B7-H4 Mjs in vitro was evaluated through phagocytosis, T-cell proliferation/ apoptosis, and cytokine production as well as in the xenografted model for in vivo analysis. Results: We found that B7-H4 expression in tumors was associated with prognosis of human glioblastoma and correlated directly with malignant grades. Mechanistically, glioma initiating CD133 cells and Mjs/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133 cells mediated immunosuppression through B7-H4 expression onMjs/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment Tcell function and tumor regression in the xenograft glioma mouse model. Conclusions: We have identified B7-H4 activation on Mjs/ microglia in the microenvironment of gliomas as an important immunosuppressive event blocking effective T-cell immune responses.

Original languageEnglish
Pages (from-to)2778-2790
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number11
DOIs
StatePublished - 1 Jun 2016

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Yao, Y., Ye, H., Qi, Z., Mo, L., Yue, Q., Baral, A., Hoon, D. S. B., Vera, J. C., Heiss, J. D., Chen, C. C., Hua, W., Zhang, J., Jin, K., Wang, Y., Mao, Y., Zang, X., & Zhou, L. (2016). B7-H4(B7x)-mediated cross-talk between glioma-initiating cells and macrophages via the IL6/JAK/STAT3 pathway lead to poor prognosis in glioma patients. Clinical Cancer Research, 22(11), 2778-2790. https://doi.org/10.1158/1078-0432.CCR-15-0858