Abstract
Angiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL) and tumor blood-vasculatures in the context of glioma progression. Paired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA) recurred as DA, DA recurred as glioblastomas (GBM), and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared. Upon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors). Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS) (HR = 4.199, 95% CI 1.522-11.584, p = 0.006). The minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3+ TILs associate with tumor angiogenesis and tumor progression in glioma patients. Our results suggest that combining antiangiogenic agents with immunotherapeutic approaches may help improve the antitumor efficacy for patients with malignant gliomas.
Highlights
Tumors recur in the resection margin in nearly 90% of CNS malignancies after primary surgery and adjuvant therapies [1, 2]
Distinct clinical outcomes were revealed in the three groups; the longest recurrencefree survival (RFS) was the diffuse astrocytomas (DA) to GBM recurrence (Table S2 and Figure S1B in Supplementary Material)
Compared to other two groups, the primary tumors in the GBM-GBM group showed relatively higher on the average density of CD34+ circles and T cells, while the DA–GBM group displayed a wider-range of T cell infiltrations (Figures 1B–E)
Summary
Tumors recur in the resection margin in nearly 90% of CNS malignancies after primary surgery and adjuvant therapies [1, 2]. The angiogenesis inhibitor Bevacizumab has been shown to prolong recurrencefree survival (RFS), no increase in overall survival (OS) was seen, in patients with newly diagnosed or recurrent GBM [6,7,8] This drug inhibits the formation of tumor blood vessels induced by vascular endothelial growth factor A (VEGF-A); increases T cell infiltrations [9, 10]; reverses expression of inhibitory molecules associated with T cell exhaustion [11]; and may directly mediate antitumor effect [12]. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL) and tumor blood-vasculatures in the context of glioma progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
