title: Immune consequences of decreasing tumor vasculature with antiangiogenic tyrosine kinase inhibitors in combination with therapeutic vaccines.
abstract: This study investigated the effects on the tumor microenvironment (TME) of combining antiangiogenic tyrosine kinase inhibitors (TKI) 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 two murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using three endothelial cell 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 lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the 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 TME, 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.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Farsaci
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Renee N
authors.initials: RN
authors.lastname: Donahue
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Coplin
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Italia
authors.initials: I
authors.lastname: Grenga
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Lepone
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. jh241d@nih.gov.
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000628:therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage*; D000077157:Sorafenib; D000077210:Sunitinib; D014614:Vaccines, Synthetic / Q000008:administration & dosage
chemical_list: D020533:Angiogenesis Inhibitors; D019496:Cancer Vaccines; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014614:Vaccines, Synthetic; D009536:Niacinamide; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib
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