Table S2.

Summary of the complementary and distinct features of the two back-to-back articles

Variables	Complementary features	Distinct features of ref. 43	Distinct features of this article	Key points
Agents	These two complementary studies show the utility of Ang-2 inhibition – potentiation of anti-VEGF therapy and extension of the animal survival – irrespective of the mode of VEGF pathway inhibition or the specificity of the inhibitory agents.	In this study, we used an Angiopoietin-2 neutralizing antibody in combination with the VEGF-TKI cediranib, which also targets other kinases, such as, c-kit, PDGFRβ, and fibroblast growth factor receptor (FGFR)-1.	In this study, we used a bispecific antibody that neutralizes both VEGF and Angiopoietin-2 (A2V). This particular therapeutic approach is a highly targeted method with limited possibility of interaction with other pathways.	The results are important for the clinical translation of both approaches (i.e., antibody versus TKI blockade of VEGF pathway), which showed distinct activity in clinical trials in other disease settings.
GBM models	The GL261 tumor model was used in both studies because it is a syngeneic tumor model. In this manner, the studies showed comparable effects of the treatments tested.	In this study, we confirmed the results in the U87 xenograft model, which shows highly abnormal tumor vessels but virtually no invasion.	In this study, we confirmed the results in the patient-derived cell line MGG8, a “stem cell-like” highly invasive GBM model that displays little vascular abnormality.	Taken together, the data from these two studies address the key issue of GBM heterogeneity, by covering a broad spectrum of malignant behavior and vascular pathophysiology in GBMs.
Immunological studies	The two approaches of dual VEGF/Ang-2 targeting confirmed the change in the tumor-associated macrophage (TAM) phenotype along the M1-M2 continuum.	The anti-Ang2/VEGFR TKI combination therapy led to a change in TAM phenotype.	Bispecific antibody A2V reprograms TAMs clearly polarized toward the anti-tumor phenotype, and decreases M2 macrophages thereby alleviating immunosuppression. Also, this study shows that these effects extend to resident microglia.	Irrespective of the approach to dual VEGF/Ang-2 inhibition, this therapy can alter the phenotype of TAMs along the M1-M2 continuum. Taken together, the results from these studies reveal the range of TAM and microglia polarization in GBM.
		This study demonstrates the causal role of TAMs in achieving a survival benefit of dual therapy. Using a CSF1 neutralizing Ab to block TAM infiltration, we show that dual therapy looses its efficacy against GBM.	This study demonstrates that achieving a survival benefit is independent of T cells by analyzing and depleting T cell population.	The two studies distinctly define two separate and complementary mechanisms involving anti-tumor immunity imparted by dual inhibition of VEGF and Ang-2 in GBM.