TriggeringTumor Immunity through AngiogenesisTargeting 55 Commentary onManning et al . , p . 3951

Whereas nascent tumors fulfill their metabolic requirements for oxygen and nutrients through diffusion from the existing vasculature, advanced lesions engender the formation of new blood vessels to support progressive tumor growth and to effectuate tissue invasion and metastasis (1). Angiogenesis reflects the complex interplay of multiple cell types, whose functions are orchestrated by an array of growth factors, adhesion molecules, and extracellular matrix components. Among the many signals contributing to tumor blood vessel development, the major vascular endothelial growth factor isoform vascular endothelial growth factor (VEGF)-A subserves a crucial role (2). VEGF-A induces endothelial cell proliferation and vascular permeability through the receptor tyrosine kinase VEGF receptor 2 (VEGF-R2; KDR, Flk-1), while stimulating the recruitment and activation of hematopoietic precursors and mature myeloid cells through VEGF-R1 (Flt-1; ref. 3). This elicited cross-talk of vascular elements and immune cells recapitulates physiologic mechanisms critical to wound healing, although tumor cells usurp these pathways to establish unrestrained angiogenesis (4, 5). In this issue of Clinical Cancer Research, Manning et al. (6) show that tumor destruction accomplished with antibody targeting of VEGF-R2 involves not only the compromise of the tumor vasculature but also the generation of antitumor T-cell responses. Moreover, in a recent volume of Clinical Cancer Research, Li et al. (7) similarly showed that the addition of anti–VEGF-A antibodies to tumor cell vaccinations intensified antitumor CTL responses, thereby resulting in increased tumor rejection. Together, these intriguing studies underscore the intimate connections between angiogenesis and tumor immunity and highlight the considerable clinical potential for combination therapies. Endogenous host reactions mediate dual and seemingly opposing roles in cancer pathogenesis (8). In some cases, the activation of innate and adaptive cytotoxic lymphocytes results in tumor suppression or the elimination of immunogenic subpopulations. Whereas the formation of clinically evident disease implies the evasion of this spontaneous immunity, the development of intratumoral T-cell infiltrates is tightly correlated with the durable responses and prolonged survival effectuated with standard oncologic therapies. Nonetheless, in contrast to this protective function, compelling epidemiologic data delineate a strong link between unresolved inflammation and tumor susceptibility. In this setting of smoldering inflammation, the mixture of cytokines and immune cells present in the tumor microenvironment supports the malignant transformation initiated by cell-intrinsic mutations in oncogenes and tumor suppressor genes. The activation of nuclear factor nB and signal transducer and activator of transcription-3 transcription factors in both tumor and host cells represents a key pathogenic event in this pathway of carcinogenesis (9, 10). Multiple components of innate immunity including macrophages, neutrophils, and mast cells cooperate to establish a robust vascular network that drives tumor cell invasion, expansion, and metastasis (11). The dysregulated immune response at the site of tumors fosters the production of various angiogenic cytokines, growth factors, and matrix metalloproteinases. The important role of innate immune cells in this regard is underscored by the attenuation of tumor progression but not initiation in macrophageand mast cell–deficient transgenic models of breast and skin carcinoma (12, 13). The coordinated recruitment of Tie-2 (the receptor for angiopoietins)–expressing macrophages, VEGF-R1–expressing hematopoietic precursors, circulating endothelial cells, and endothelial progenitor cells all contribute to the formation of an angiogenic niche (14–16). Moreover, the interleukin-23/interleukin-17 network, which functions as a master regulator of tumor promoting inflammation, concomitantly inhibits intratumoral T-cell infiltration and cytotoxicity, thereby further compromising host defense (17, 18). The central role of VEGF-A/VEGF-R2 signaling in tumor angiogenesis has motivated the crafting of therapeutic strategies to antagonize this pathway. Bevacizumab (Avastin), a humanized anti–VEGF-A murine monoclonal antibody, is the first Food and Drug Administration–approved antiangiogenic agent for cancer. Bevacizumab as a single agent manifests only minimal antitumor activities in multiple diseases; however, in conjunction with cytotoxic chemotherapy, clinically meaningful effects are achieved. A large, randomized, phase III trial in metastatic colorectal carcinoma patients revealed an increased response rate and improved survival for the addition of bevacizumab to irinotecan, 5-fluorouracil, and leucovorin compared with chemotherapy alone (19). This important validation of VEGF-A as an antitumor target has catalyzed the exploration of many other approaches to blocking angiogenesis, including small-molecule inhibitors of the VEGF-A receptor tyrosine kinases and other biologics directed toward the ligand or receptors. Within this context, the report of Manning and colleagues provides new insights into the therapeutic activities of anti– VEGF-R2 monoclonal antibodies. Rather than using human xenografts in immunodeficient hosts, as in earlier studies, these investigators examined the effects of anti–VEGF-R2 antibodies in immunocompetent mice harboring syngeneic breast cancer cells derived from Her2/neu transgenic animals (6). This experimental strategy revealed that although antibody administration reduced angiogenesis, as determined by immunohistochemistry for CD31, it also provoked an impressive CD4 The Clinical Connection