Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.

Chronic pelvic pain (CPP) is a significant public health problem with 1 million affected women in the UK. Although many pathologies are associated with CPP, the pain experienced is often disproportionate to the extent of disease identified and frequently no pathology is found (chronic pelvic pain syndrome). The central nervous system (CNS) is central to the experience of pain and chronic pain conditions in general are associated with alterations in both the structure and function of the CNS. This review describes the available evidence for central changes in association with conditions presenting with CPP. A detailed literature search was performed to identify relevant papers, however, this is not a systematic review. CPP is associated with central changes similar to those identified in other pain conditions. Specifically these include, alterations in the behavioural and central response to noxious stimulation, changes in brain structure (both increases and decreases in the volume of specific brain regions), altered activity of both the hypothalamic–pituitary–adrenal axis and the autonomic nervous system (ANS) and psychological distress. The evidence reviewed in this paper demonstrates that CPP is associated with significant central changes when compared with healthy pain-free women. Moreover, the presence of these changes has the potential to both exacerbate symptoms and to predispose these women to the development of additional chronic conditions. These findings support the use of adjunctive medication targeting the CNS in these women.

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

Expansion of antigen-experienced CD8⁺ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer¹. Interleukin-2 (IL-2) acts as a key regulator of CD8⁺ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability^2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE₂), a known negative regulator of immune response in the tumour microenvironment^4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8⁺ TILs via the PGE₂ receptors EP2 and EP4. Mechanistically, PGE₂ inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ_c chain, resulting in defective assembly of IL-2Rβ–IL2Rγ_c membrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE₂ signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE₂ in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.

Cancer-specific TCF1⁺ stem-like CD8⁺ T cells can drive protective anticancer immunity through expansion and effector cell differentiation^1–4; however, this response is dysfunctional in tumours. Current cancer immunotherapies^2,5–9 can promote anticancer responses through TCF1⁺ stem-like CD8⁺ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1⁺CD8⁺ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE₂) restricts the proliferative expansion and effector differentiation of TCF1⁺CD8⁺ T cells within tumours, which promotes cancer immune escape. PGE₂ does not affect the priming of TCF1⁺CD8⁺ T cells in draining lymph nodes. PGE₂ acts through EP₂ and EP₄ (EP₂/EP₄) receptor signalling in CD8⁺ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1⁺ tumour-infiltrating CD8⁺ T lymphocytes (TILs). Ablation of EP₂/EP₄ signalling in cancer-specific CD8⁺ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE₂-mediated inhibition of TCF1⁺ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1⁺ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE₂–EP₂/EP₄ axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.