Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment. A compelling body of evidence indicates that ...anti-angiogenic therapy has the capacity to ameliorate antitumour immunity owing to the inhibition of various immunosuppressive features of angiogenesis. Hence, combinations of anti-angiogenic agents and immunotherapy are currently being tested in >90 clinical trials and 5 such combinations have been approved by the FDA in the past few years. In this Perspective, we describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as the vascular counterpart of immune checkpoints. We review the antitumour immunity-promoting effects of anti-angiogenic agents and provide an update on the current clinical successes achieved when these agents are combined with immune checkpoint inhibitors. Finally, we propose that anti-angiogenic agents are immunotherapies - and vice versa - and discuss future research priorities.
Abstract The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and ...also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy.
Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and ...secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Antibody targeting of extracellular vimentin shows inhibition of angiogenesis in vitro and in vivo. Effective and safe inhibition of angiogenesis and tumor growth in several preclinical and clinical studies is demonstrated using a vaccination strategy against extracellular vimentin. Targeting vimentin induces a pro-inflammatory condition in the tumor, exemplified by induction of the endothelial adhesion molecule ICAM1, suppression of PD-L1, and altered immune cell profiles. Our findings show that extracellular vimentin contributes to immune suppression and functions as a vascular immune checkpoint molecule. Targeting of extracellular vimentin presents therefore an anti-angiogenic immunotherapy strategy against cancer.
Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to ...tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFκB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFκB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.
The concept of antiangiogenic therapy in cancer treatment has led to the approval of different agents, most of them targeting the well known vascular endothelial growth factor pathway. Despite ...promising results in preclinical studies, the efficacy of antiangiogenic therapy in the clinical setting remains limited. Recently, awareness has emerged on resistance to antiangiogenic therapies. It has become apparent that the intricate complex interplay between tumors and stromal cells, including endothelial cells and associated mural cells, allows for escape mechanisms to arise that counteract the effects of these targeted therapeutics. Here, we review and discuss known and novel mechanisms that contribute to resistance against antiangiogenic therapy and provide an outlook to possible improvements in therapeutic approaches.
To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with VEGF-targeted therapy.
Phase II trials of VEGF pathway-targeted therapy given before ...cytoreductive surgery were carried out with metastatic RCC patients with the primary tumor in situ to investigate the necessity of nephrectomy. Primary tumor tissues were obtained and assessed for angiogenesis parameters. Results were compared with similar analyses on untreated tumors.
Sunitinib or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor. Also, an increase in vascular pericyte coverage was found in sunitinib-pretreated tumors, consistent with efficient angiogenesis inhibition. Expression of several key regulators of angiogenesis was found to be suppressed in pretreated tissues, among which VEGFR-1 and VEGFR-2, angiopoietin-1 and angiopoietin-2 and platelet-derived growth factor-B. In addition, apoptosis in tumor and endothelial cells was induced. Interestingly, in sunitinib-pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed, which was not the case in bevacizumab-pretreated tumors. A positive correlation with the interval between halting the therapy and surgery was found, suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment.
This study describes, for the first time, the angiostatic response in human primary renal cancers at the tissue level upon treatment with VEGF-targeted therapy. Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated endothelial cell proliferation. The results of this study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors.
Abstract Several angiogenesis inhibitors are currently used in the clinic for treatment of cancer. While anti-angiogenesis treatment can improve treatment outcome, the overall benefit on patient ...survival is still rather limited. This is partially explained by intrinsic or acquired resistance of tumor cells to angiostatic drugs. In addition, it has become evident that extrinsic mechanisms are also involved in resistance to angiostatic therapy. Most of these extrinsic mechanisms reside in the tumor stroma, which is composed of different cell types, including endothelial (progenitor) cells, smooth muscle cells, pericytes, (myo)fibroblasts, immune cells and platelets. In the current review, we describe the role of these stromal cells in the resistance to anti-angiogenic drugs and discuss possible strategies to overcome resistance and enhance the efficacy of angiostatic therapy.
Therapeutically guided multidrug optimization (TGMO) technology, composed of experimental testing and in silico modelling, allowed identification of synergistic and selective low‐dose optimized drug ...combinations (ODCs) active in multiple colorectal carcinoma models. The mechanisms of action of the ODCs was established using transcriptome sequencing and phosphoproteomic analyses. Our results indicate that simultaneous multitarget inhibition of important deregulated pathways has strong therapeutic potential and translational value between tumor types.
The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late‐stage disease. We employed the phenotypically driven therapeutically guided multidrug optimization (TGMO) technology to identify optimized drug combinations (ODCs) in CRC. We identified low‐dose synergistic and selective ODCs for a panel of six human CRC cell lines also active in heterotypic 3D co‐culture models. Transcriptome sequencing and phosphoproteome analyses showed that the mechanisms of action of these ODCs converged toward MAP kinase signaling and cell cycle inhibition. Two cell‐specific ODCs were translated to in vivo mouse models. The ODCs reduced tumor growth by ~80%, outperforming standard chemotherapy (FOLFOX). No toxicity was observed for the ODCs, while significant side effects were induced in the group treated with FOLFOX therapy. Identified ODCs demonstrated significantly enhanced bioavailability of the individual components. Finally, ODCs were also active in primary cells from CRC patient tumor tissues. Taken together, we show that the TGMO technology efficiently identifies selective and potent low‐dose drug combinations, optimized regardless of tumor mutation status, outperforming conventional chemotherapy.
Galectins are carbohydrate binding proteins that function in many key cellular processes. We have previously demonstrated that galectins are essential for tumor angiogenesis and their expression is ...associated with disease progression. Targeting galectins is therefore a potential anti‐angiogenic and anti‐cancer strategy. Here, we used a rational approach to generate antibodies against a specific member of this conserved protein family, i.e. galectin‐1. We characterized two novel mouse monoclonal antibodies that specifically react with galectin‐1 in human, mouse and chicken. We demonstrate that these antibodies are excellent tools to study galectin‐1 expression and function in a broad array of biological systems. In a potential diagnostic application, radiolabeled antibodies showed specific targeting of galectin‐1 positive tumors. In a therapeutic setting, the antibodies inhibited sprouting angiogenesis in vitro and in vivo, underscoring the key function of galectin‐1 in this process.
What's New?
Galectins are carbohydrate‐binding proteins with an essential role in tumor angiogenesis and whose expression is associated with disease progression. Based on a rational approach, here the authors generated and characterized two novel mouse monoclonal antibodies that specifically react with galectin‐1 in human, mouse and chicken. The antibodies are promising tools to study galectin‐1 expression and function in a broad array of biological systems. In a potential diagnostic application, radiolabeled antibodies showed specific targeting of galectin‐1 positive tumors. In a therapeutic setting, the antibodies inhibited sprouting angiogenesis in vitro and in vivo, underscoring the key function of galectin‐1 in this process.
Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the ...development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease severity, and significant inflammatory cell infiltration. Angiogenesis is therefore an interesting target for the development of new therapeutic approaches as well as disease monitoring strategies in RA. To this end, nuclear imaging modalities represent valuable non-invasive tools that can selectively target molecular markers of angiogenesis and accurately and quantitatively track molecular changes in multiple joints simultaneously. This systematic review summarizes the imaging markers used for single photon emission computed tomography (SPECT) and/or positron emission tomography (PET) approaches, targeting pathways and mediators involved in synovial neo-angiogenesis in RA.
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