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Head and Neck Vascular Anomalies: A Practical Case-Based Approach is a useful guide to the management of lesions caused by vascular anomalies, providing specific treatment algorithms for their management. This book offers consistent and straightforward techniques to the more frequently encountered and some of the more difficult vascular anomalies. Coming from the world-renowned vascular anomalies center at the University of Arkansas for Medical Sciences, known for its clinical expertise and multi-disciplinary approach, editors Dr. Suen and Dr. Richter have over 40 years combined experience in treating these lesions. With contributed chapters from international leaders in the field, the editors present a practical guide, based upon clinical and scientific evidence, on the approach to diagnosis and management to each vascular anomaly based upon type, extent and location. The book provides a case-based approach to simple and complex lesions. Initial steps for diagnosis followed by a recommended treatment approach is presented with photographs, imaging and step-by-step illustrations to surgical or alternative therapies. All presented information is based upon current literature, providing a timeless and seamless algorithm to each lesion. Each case begins with a diagnostic approach, followed by next best steps to imaging treatment and follow up. With the increasing number of vascular anomaly centers, and physicians participating in the care of these patients along with the recent advancements and consistency in managing these patients, the timing for this text is ideal.

The stimulator of interferon genes (STING) signaling pathway is a critical link between innate and adaptive immunity, and induces anti-tumor immune responses. STING is expressed in vasculatures, but its role in tumor angiogenesis has not been elucidated. Here we investigated STING-induced tumor vascular remodeling and the potential of STING-based combination immunotherapy. Endothelial STING expression was correlated with enhanced T-cell infiltration and prolonged survival in human colon and breast cancer. Intratumoral STING activation with STING agonists (cGAMP or RR-CDA) normalized tumor vasculatures in implanted and spontaneous cancers, but not in STING-deficient mice. These were mediated by upregulation of type I/II interferon genes and vascular stabilizing genes (e.g., Angpt1, Pdgfrb, and Col4a). STING in non-hematopoietic cells is as important as STING in hematopoietic cells to induce a maximal therapeutic efficacy of exogenous STING agonist. Vascular normalizing effects of STING agonists were dependent on type I interferon signaling and CD8+ T cells. Notably, STING-based immunotherapy was maximally effective when combined with VEGFR2 blockade and/or immune checkpoint blockade (αPD-1 or αCTLA-4), leading to complete regression of immunotherapy-resistant tumors. Our data show that intratumoral STING activation can normalize tumor vasculature and the tumor microenvironment, providing a rationale for combining STING-based immunotherapy and anti-angiogenic therapy.

The cross-talk between immune cells and blood vessel endothelial cells promotes pericyte coverage and decreases hypoxia in mouse tumour models, and correlative evidence suggests that these processes influence cancer prognosis in humans. Normalizing tumour vasculature Tumours often develop with abnormal vasculature, characterized among other things by lower pericyte coverage of blood vessels, as well as leaky vessels that result in a hypoxic environment. Abnormal vessels limit immune infiltration and CD4 T cells can regulate angiogenesis. Using mouse models, the authors further dissect this crosstalk between immune cells and blood vessels in cancer, and describe a role for immune cells in normalizing the vasculature of tumours. The crosstalk between CD4 T cells and endothelial cells promotes pericyte coverage and decreases hypoxia, and correlative evidence suggests that these processes influence cancer prognosis in humans. The authors postulate that interventions that foster CD4 T-cell function, such as immune checkpoint blockade, also have a beneficial effect by normalizing the tumour vasculature. Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis 1 , 2 . This paradox may be resolved by vessel normalization 3 , which involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia 3 . Although these processes alter tumour progression, their regulation is poorly understood. Here we show that type 1 T helper (T H 1) cells play a crucial role in vessel normalization. Bioinformatic analyses revealed that gene expression features related to vessel normalization correlate with immunostimulatory pathways, especially T lymphocyte infiltration or activity. To delineate the causal relationship, we used various mouse models with vessel normalization or T lymphocyte deficiencies. Although disruption of vessel normalization reduced T lymphocyte infiltration as expected 4 , reciprocal depletion or inactivation of CD4 + T lymphocytes decreased vessel normalization, indicating a mutually regulatory loop. In addition, activation of CD4 + T lymphocytes by immune checkpoint blockade increased vessel normalization. T H 1 cells that secrete interferon-γ are a major population of cells associated with vessel normalization. Patient-derived xenograft tumours growing in immunodeficient mice exhibited enhanced hypoxia compared to the original tumours in immunocompetent humans, and hypoxia was reduced by adoptive T H 1 transfer. Our findings elucidate an unexpected role of T H 1 cells in vasculature and immune reprogramming. T H 1 cells may be a marker and a determinant of both immune checkpoint blockade and anti-angiogenesis efficacy.

High endothelial venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting high levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders (bacterial and viral infections) and alterations in the body’s own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing high levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn’s disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79+ tumor-associated HEVs (TA-HEVs) are frequently found in human tumors in CD3+ T cell-rich areas or CD20+ B-cell rich tertiary lymphoid structures (TLSs). TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models.

Hypoxia arises frequently in solid tumors and is a poor prognostic factor as it promotes tumor cell proliferation, invasion, angiogenesis, therapy resistance, and metastasis. Notably, there are two described forms of hypoxia present in a growing tumor: chronic hypoxia, caused by abnormal tumor vasculature, and intermittent hypoxia, caused by transient perfusion facilitated by tumor-supplying blood vessels. Here, we demonstrate that intermittent hypoxia, but not chronic hypoxia, endows breast cancer cells with greater metastatic potential. Using an immunocompetent and syngeneic murine model of breast cancer, we show that intermittent hypoxia enhances metastatic seeding and outgrowth in lungs in vivo. Furthermore, exposing mammary tumor cells to intermittent hypoxia promoted clonal diversity, upregulated metastasis-associated gene expression, induced a pro-tumorigenic secretory profile, increased stem-like cell marker expression, and gave rise to tumor-initiating cells at a relatively higher frequency. This work demonstrates that intermittent hypoxia, but not chronic hypoxia, induces a number of genetic, molecular, biochemical, and cellular changes that facilitate tumor cell survival, colonization, and the creation of a permissive microenvironment and thus enhances metastatic growth.

Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM); however, a mechanistic connection in vivo has not been established. The purpose of this study is to characterize the effects of murine CMV (MCMV) on GBM growth in murine models. Syngeneic GBM models were established in mice perinatally infected with MCMV. We found that tumor growth was markedly enhanced in MCMV+ mice, with a significant reduction in overall survival compared with that of controls (P < 0.001). We observed increased angiogenesis and tumor blood flow in MCMV+ mice. MCMV reactivation was observed in intratumoral perivascular pericytes and tumor cells in mouse and human GBM specimens, and pericyte coverage of tumor vasculature was strikingly augmented in MCMV+ mice. We identified PDGF-D as a CMV-induced factor essential for pericyte recruitment, angiogenesis, and tumor growth. The antiviral drug cidofovir improved survival in MCMV+ mice, inhibiting MCMV reactivation, PDGF-D expression, pericyte recruitment, and tumor angiogenesis. These data show that MCMV potentiates GBM growth in vivo by increased pericyte recruitment and angiogenesis due to alterations in the secretome of CMV-infected cells. Our model provides evidence for a role of CMV in GBM growth and supports the application of antiviral approaches for GBM therapy.

Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti-cytotoxic T lymphocyte-associated protein 4 or anti-programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, CD8+ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8+ T cell accumulation and IFN-γ production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.

Cancer cells have diverse mechanisms for utilizing the vasculature; they can initiate the formation of new blood vessels from preexisting ones (sprouting angiogenesis) or they can form cohesive interactions with the abluminal surface of preexisting vasculature in the absence of sprouting (co-option). The later process has received renewed attention due to the suggested role of blood vessel co-option in resistance to antiangiogenic therapies and the reported perivascular positioning and migratory patterns of cancer cells during tumor dormancy and invasion, respectively. However, only a few molecular mechanisms have been identified that contribute to the process of co-option and there has not been a formal survey of cell lines and laboratory models that can be used to study co-option in different organ microenvironments; thus, we have carried out a comprehensive literature review on this topic and have identified cell lines and described the laboratory models that are used to study blood vessel co-option in cancer. Put into practice, these models may help to shed new light on the molecular mechanisms that drive blood vessel co-option during tumor dormancy, invasion, and responses to different therapies.

Immune checkpoint blockade therapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to insufficient T cell infiltration in tumors. Here we show that expression of mitochondrial uncoupling protein 2 (UCP2) in tumor cells determines the immunostimulatory feature of the tumor microenvironment (TME) and is positively associated with prolonged survival. UCP2 reprograms the immune state of the TME by altering its cytokine milieu in an interferon regulatory factor 5-dependent manner. Consequently, UCP2 boosts the conventional type 1 dendritic cell- and CD8 + T cell-dependent anti-tumor immune cycle and normalizes the tumor vasculature. Finally we show, using either a genetic or pharmacological approach, that induction of UCP2 sensitizes melanomas to programmed cell death protein-1 blockade treatment and elicits effective anti-tumor responses. Together, this study demonstrates that targeting the UCP2 pathway is a potent strategy for alleviating the immunosuppressive TME and overcoming the primary resistance of programmed cell death protein-1 blockade. The tumor microenvironment is central to the immunogenicity of tumors. Ho and colleagues show that activity of the mitochondrial protein UCP2 in tumors enhances their immunogenicity through the recruitment of dendritic cells and reprogramming of this microenvironment.

Metastasis is currently becoming a major clinical concern, due to its potential to cause therapeutic resistance. Its development involves a series of phases that describe the metastatic cascade: preparation of the pre-metastatic niche, epithelial–mesenchymal transition, dissemination, latency and colonization of the new tissue. In the last few years, new therapeutic targets, such as integrins, are arising to face this disease. Integrins are transmembrane proteins found in every cell that have a key role in the metastatic cascade. They intervene in adhesion and intracellular signaling dependent on the extracellular matrix and cytokines found in the microenvironment. In this case, integrins can initiate the epithelial–mesenchymal transition, guide the formation of the pre-metastatic niche and increase tumor migration and survival. Integrins also take part in the tumor vascularization process necessary to sustain metastasis. This fact emphasizes the importance of inhibitory therapies capable of interfering with the function of integrins in metastasis.