Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab

Abstract

Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post‐Bev recurrent tumors from 9 patients were included. The expression of programmed cell death‐1 (PD‐1)/PD ligand‐1 (PD‐L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD‐L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD‐1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor‐associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post‐Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long‐term Bev therapy.

The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications

“…Anti-angiogenic therapy may change the TME into an immunological favorable "hot" microenvironment. Bev suppresses immunosuppressive cells including TAMs, Tregs, and MDSCs, and improves the migratory capacity of CTLs [14]. Theoretically, Bev could enhance the effect of PD-1/PD-L1 inhibitors (Fig.…”

“…Furthermore, in the recurrent stage after anti-angiogenic therapy, the status of immunosuppressive cells and immune checkpoint molecules is also highly controversial ( Table 2). VEGF-targeted therapy can lead to either tumor oxygenation or tumor hypoxia [14,61,107]. Therefore, both an immunesupportive TME in normoxic conditions and a hypoxiainduced immunosuppressive TME have been reported after VEGF-targeted therapy [14,61,107].…”

“…VEGF-targeted therapy can lead to either tumor oxygenation or tumor hypoxia [14,61,107]. Therefore, both an immunesupportive TME in normoxic conditions and a hypoxiainduced immunosuppressive TME have been reported after VEGF-targeted therapy [14,61,107]. Tregs in the peripheral blood are increased in patients with recurrent GBs after development of resistance to VEGFR inhibitors [89].…”

“…Bev downregulates the expression of PD-1 and PD-L1 immune checkpoint molecules, suppresses the infiltration of TAMs and Tregs, and increases CTL infiltration. Importantly, the conditions are sustained during long-term Bev usage [14]. VEGF persistently contributes to tumor growth, even if secondary signaling pathways are upregulated.…”

“…VEGF is induced by hypoxia through a hypoxia-inducible factor 1 alpha (HIF-1α)-depending pathway, which contributes to immune suppression in the TME [10]. Therefore, anti-VEGF (bevacizumab; Bev) or VEGF receptor (VEGFR)-targeted (sunitinib, sorafenib) agents as a cancer treatment induce not only anti-angiogenic effects, but also immune-supportive effects [11][12][13][14]. Recently, the significance of the PD-1/PD-L1 immune checkpoint system has received attention in several types of tumors [6,7].…”