Abstract
A lack of explicit early clinical signs and effective screening measures mean that ovarian cancer (OC) often presents as advanced, incurable disease. While conventional treatment combines maximal cytoreductive surgery and platinum-based chemotherapy, patients frequently develop chemoresistance and disease recurrence. The clinical application of immune checkpoint blockade (ICB) aims to restore anti-cancer T-cell function in the tumour microenvironment (TME). Disappointingly, even though tumour infiltrating lymphocytes are associated with superior survival in OC, ICB has offered limited therapeutic benefits. Herein, we discuss specific TME features that prevent ICB from reaching its full potential, focussing in particular on the challenges created by immune, genomic and metabolic alterations. We explore both recent and current therapeutic strategies aiming to overcome these hurdles, including the synergistic effect of combination treatments with immune-based strategies and review the status quo of current clinical trials aiming to maximise the success of immunotherapy in OC.
Highlights
Epithelial ovarian cancer (OC) is the most fatal gynaecological malignancy with around 7400 new diagnoses per year in the United Kingdom alone, and a 5-year overall survival (OS) rate of only 45% [1], prompting efforts towards developing novel treatments
Given that cytotoxic T lymphocyte antigen 4 (CTLA-4) and PD-1/PD-L1 pathways create a mechanism through which cancer cells avoid anti-tumour responses, the blockade of these pathways aimed at reversing T-cell exhaustion, and reinvigorating the anti-cancer response has been central to the development of novel therapies
A contributing factor to this phenomenon is a progressive loss of peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1-α (PGC-1α) on tumour infiltrating lymphocyte (TIL) driven by chronic AKT signalling from tumourspecific T-cells [244]
Summary
Epithelial ovarian cancer (OC) is the most fatal gynaecological malignancy with around 7400 new diagnoses per year in the United Kingdom alone, and a 5-year overall survival (OS) rate of only 45% [1], prompting efforts towards developing novel treatments One such area is the rise of immunotherapy as a new therapeutic strategy that is being deployed across a broad spectrum of malignancies. As immune cell differentiation and function require energy, the competing metabolic demands of both tumour and stromal cells concurrently impair effector T-cell function by overexposure to suppressive metabolites and essential nutrient starvation [8] As a result, both innate and adaptive immune responses are blunted, which amplifies tumour tolerance, requiring novel approaches to circumvent these barriers by using alternative immune strategies or combinatorial approaches. We discuss novel strategies designed to overcome these hurdles and summarise ongoing clinical trials aiming to apply immunotherapy in the context of OC management
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