Abstract
Simple SummaryImmunotherapies have changed the way we treat cancer and, while some patients have benefitted greatly, there are still those that do not respond to therapy. Understanding why some patients respond to therapy and others do not is critical in developing new immunotherapeutic strategies. The increasing awareness of the importance of investigating the tumour in its entirety, including the surrounding tissue and role of various immune cells is helping to differentiate responders and non-responders. In addition, the resolution gained by the development of sophisticated bioinformatic technologies allows for a deeper understanding of the complex roles of individual cells in the tumour. This advancement will be critical for the development of novel therapies to treat cancer.Immunotherapy has revolutionised the treatment of cancers by exploiting the immune system to eliminate tumour cells. Despite the impressive response in a proportion of patients, clinical benefit has been limited thus far. A significant focus to date has been the identification of specific markers associated with response to immunotherapy. Unfortunately, the heterogeneity between patients and cancer types means identifying markers of response to therapy is inherently complex. There is a growing appreciation for the role of the tumour microenvironment (TME) in directing response to immunotherapy. The TME is highly heterogeneous and contains immune, stromal, vascular and tumour cells that all communicate and interact with one another to form solid tumours. This review analyses major cell populations present within the TME with a focus on their diverse and often contradictory roles in cancer and how this informs our understanding of immunotherapy. Furthermore, we discuss the role of integrated omics in providing a comprehensive view of the TME and demonstrate the potential of leveraging multi-omics to decipher the underlying mechanisms of anti-tumour immunity for the development of novel immunotherapeutic strategies.
Highlights
It is an accepted view that solid cancers comprise malignant cells but a complex and dynamic network of tumour cells, immune cells, endothelial cells and vasculature, fibroblasts and an extracellular matrix containing various cytokines, chemokines, hormones, and growth factors
Solid tumours are a complex arrangement of cells, vessels, and soluble factors with both pro- and anti-tumoral activity, which vary greatly both within and across cancer types and patients
To stratify patients to determine which may respond to immunotherapies we rely upon categorising tumours as ‘hot’ or ‘cold. this oversimplification of the nuanced and context-dependent nature of the tumour microenvironment (TME) leaves gaps in our understanding of why some patients do not respond to immunotherapy and other do despite having ‘hot’ or ‘cold’ tumours, respectively
Summary
It is an accepted view that solid cancers comprise malignant cells but a complex and dynamic network of tumour cells, immune cells, endothelial cells and vasculature, fibroblasts and an extracellular matrix containing various cytokines, chemokines, hormones, and growth factors. Hot tumours in general are considered more responsive to immunotherapies than their cold counterparts. A binary approach does not consider all the nuances of the TME, or the promiscuity and plasticity of the cells within. Such environments are constantly evolving under pressure from the immune system and the continuous growth of the cancer itself. Generating a deeper understanding of the TME is critical to developing strategies to induce responses in all patients, those who currently do not respond to therapy despite having a ‘hot’ tumour
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