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Abstract
Simple SummaryAlthough immunotherapy has given the highest rate of improvement in cancer treatment in recent years, there is an urgent need to further improve its efficacy. Numerous strategies aim to transform non-responsive, immunosuppressive tumours into sensitive, immunopermissive tumours. The modulation of the tumour microenvironment, and especially the tumour vasculature offers opportunities for improved sensitivity to immunotherapy. Modulation of tumour blood vessels can enhance tumour oxygenation and T cell infiltration. Additionally, maturation of tumour blood vessels is thought to be involved in the efficient delivery of therapeutic agents. This review compiles the current strategies of vascular modulation to improve the efficacy of different immunotherapies: PD-1/PD-L1 and CTLA-4 antibodies, CAR T cells and cancer vaccines.Several strategies have been developed to modulate the tumour vasculature for cancer therapy including anti-angiogenesis and vascular normalisation. Vasculature modulation results in changes to the tumour microenvironment including oxygenation and immune cell infiltration, therefore lending itself to combination with cancer therapy. The development of immunotherapies has led to significant improvements in cancer treatment. Particularly promising are immune checkpoint blockade and CAR T cell therapies, which use antibodies against negative regulators of T cell activation and T cells reprogrammed to better target tumour antigens, respectively. However, while immunotherapy is successful in some patients, including those with advanced or metastatic cancers, only a subset of patients respond. Therefore, better predictors of patient response and methods to overcome resistance warrant investigation. Poor, or periphery-limited, T cell infiltration in the tumour is associated with poor responses to immunotherapy. Given that (1) lymphocyte recruitment requires leucocyte–endothelial cell adhesion and (2) the vasculature controls tumour oxygenation and plays a pivotal role in T cell infiltration and activation, vessel targeting strategies including anti-angiogenesis and vascular normalisation in combination with immunotherapy are providing possible new strategies to enhance therapy. Here, we review the progress of vessel modulation in enhancing immunotherapy efficacy.
Highlights
The dynamics between tumour cells and their environment is regulated by several cell types such as cancer-associated fibroblasts (CAFs) and tumour infiltrating leukocytes (TILs) [5]
The formation of new blood vessels from the pre-existing vasculature is the main method of neovascularisation in tumours with their hypoxic and necrotic regions acting as inducers of angiogenesis
It has been shown that the combination of immunotherapy and anti-angiogenic therapy increases High Endothelial Venules (HEVs) formation in breast and pancreatic experimental tumours, enhancing T cell infiltration [162]
Summary
Immune modulation has provided a wide range of new potential therapies for many cancer types with some exciting advances in many malignancies [1,2,3]. Antigen binding to corresponding B or T cell receptors promotes the activation of the immune response as well as the generation of memory cells. PD1-PD-L1 interaction blockade has been generally successful in clinical trials for melanoma, NSCLC, renal cell cancer and ovarian cancer, the same treatments have not provided objective responses in other cancers including pancreat-ic cancer patients [14]. These TCR sequences can be captured from neoantigen-specific T cells and are being tested in preclinical models of acute myeloid leukaemia or solid tumours [32]. Other promising immunotherapies include cancer vaccines which prime the immune system to target one or more tumour-specific antigens. The aim of cancer vaccines is to induce tumour regression by stimulation of the patient’s adaptative immune response They involve tumour antigens that activate dendritic cells [33]. In 2010, it was the first cancer vaccine to be FDA approved [34]
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