This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKIs) with therapeutic vaccines and, in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TILs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. Combination therapy decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. Combination therapy increased TILs, including tumor antigen-specific CD8 T cells, and elevated expression of the activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increased number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy.
- Received April 22, 2014.
- Revision received July 1, 2014.
- Accepted July 22, 2014.
- Copyright © 2014, American Association for Cancer Research.