Nutrient deprivation and hypoxia alter T cell immune checkpoint expression: potential impact for immunotherapy.

Aim: Use of immune checkpoint blockade to enhance T cell-mediated immunity within the hostile tumour microenvironment (TME) is an attractive approach in oesophageal adenocarcinoma (OAC). This study explored the effects of the hostile TME, including nutrient deprivation and hypoxia, on immune checkpoint (IC) expression and T cell phenotypes, and the potential use of nivolumab to enhance T cell function under such conditions.

Methods And Results: ICs were upregulated on stromal immune cells within the tumour including PD-L2, CTLA-4 and TIGIT.

FLOT and CROSS chemotherapy regimens alter the frequency of CD27 and CD69 T cells in oesophagogastric adenocarcinomas: implications for combination with immunotherapy.

Combining immunostimulatory chemotherapies with immunotherapy is an attractive strategy to enhance treatment responses in oesophagogastric junctional adenocarcinoma (OGJ). This study investigates the immunostimulatory properties of FLOT, CROSS and MAGIC chemotherapy regimens in the context of OGJ using in vitro and ex vivo models of the treatment-naïve and post-chemotherapy treated tumour microenvironment. FLOT and CROSS chemotherapy regimens increased surrogate markers of immunogenic cell death (HMGB1 and HLA-DR), whereas the MAGIC treatment regimen decreased HMGB1 and HLA-DR on OGJ cells (markedly for epirubicin).

The immune response to major gastrointestinal cancer surgery and potential implications for adjuvant immunotherapy.

The perioperative period theoretically is a critical time of opportunity for the progression of pre-existing tumour micrometastasis. Therefore,the timing of introducing cancer therapies including chemotherapy, radiation therapy and immunotherapies in the postoperative period is important. A thorough exploration of the perioperative immune events at a cellular level in combination with an intricate review of available clinical rials was conducted to extrapolate the effects of oncological surgery on the perioperative immune milieu.

Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma.

Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting 'cold' tumours into 'hot' tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics.

PD-1 and TIGIT blockade differentially affect tumour cell survival under hypoxia and glucose deprived conditions in oesophageal adenocarcinoma; implications for overcoming resistance to PD-1 blockade in hypoxic tumours.

Recent studies have demontrated that immune checkpoint receptors are expressed on the surface of oesophageal adenocarcinoma (OAC) cells and might confer a survival advantage. This study explores the role of PD-1 and TIGIT signalling in OAC cells in either promoting or inhibiting the survival of OAC cells under characteristic features of the tumour microenvironment including nutrient-deprivation and hypoxia. PD-1 and TIGIT are expressed in normal and pre-malignant oesophageal epithelial cells and this expression significantly decreases along the normal- Barrett's Oesophagus- OAC disease sequence.

The Impact of Esophageal Oncological Surgery on Perioperative Immune Function; Implications for Adjuvant Immune Checkpoint Inhibition.

Background: Immune checkpoint inhibitors (ICIs) are being investigated for their role as an adjunct in the multimodal treatment of esophageal adenocarcinoma (EAC). The most effective time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumor immunity perioperatively to help inform the optimal timing of ICIs into current standards of care for EAC patients.

Impact of COVID-19 on the Diagnosis and Surgical Treatment of Colorectal Cancer: A National Perspective.

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The Prognostic Value of the Lymph Node in Oesophageal Adenocarcinoma; Incorporating Clinicopathological and Immunological Profiling.

Response rates to the current gold standards of care for treating oesophageal adenocarcinoma (OAC) remain modest with 15-25% of patients achieving meaningful pathological responses, highlighting the need for novel therapeutic strategies. This study consists of immune, angiogenic, and inflammatory profiling of the tumour microenvironment (TME) and lymph node microenvironment (LNME) in OAC. The prognostic value of nodal involvement and clinicopathological features was compared using a retrospective cohort of OAC patients ( = 702).

Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers.

The malfeasant role of the hypoxic tumour microenvironment (TME) in cancer progression was recognized decades ago but the exact mechanisms that augment the hallmarks of cancer and promote treatment resistance continue to be elucidated. Gastroesophageal cancers (GOCs) represent a major burden of worldwide disease, responsible for the deaths of over 1 million people annually. Disentangling the impact of hypoxia in GOCs enables a better overall understanding of the disease pathogenesis while shining a light on novel therapeutic strategies and facilitating precision treatment approaches with the ultimate goal of improving outcomes for patients with these diseases.

The tumour immune microenvironment in oesophageal cancer.

Oesophageal cancer (OC) is an inflammation-associated malignancy linked to gastro-oesophageal reflux disease, obesity and tobacco use. Knowledge of the microenvironment of oesophageal tumours is relevant to our understanding of the development of OC and its biology, and has major implications for understanding the response to standard therapies and immunotherapies, as well as for uncovering novel targets. In this context, we discuss what is known about the TME in OC from tumour initiation to development and progression, and how this is relevant to therapy sensitivity and resistance in the two major types of OC.

Chemotherapy regimens induce inhibitory immune checkpoint protein expression on stem-like and senescent-like oesophageal adenocarcinoma cells.

Use of immune checkpoint inhibitors (ICIs) with chemotherapy to enhance responses in oesophageal adenocarcinoma (OAC) is an attractive approach. We identified subpopulations of OAC cells expressing inhibitory immune checkpoint (IC) ligands (PD-L1, PD-L2 and CD160) and receptors (PD-1, TIGIT, TIM-3, LAG-3 and A2aR) in vitro and in ex vivo biopsies. Combination chemotherapy regimens FLOT and CROSS promote a more immune-resistant phenotype through upregulation of IC ligands and receptors on OAC cells in vitro.

Radiation and Immunotherapy in Upper Gastrointestinal Cancers: The Current State of Play.

Radiotherapy remains one of the contemporary cornerstones of cancer treatment in the neoadjuvant, curative, adjuvant and palliative settings, either in isolation or as a multimodal approach. Moreover, recent advances in targeted immune checkpoint therapy have firmly established immunotherapy as the fourth pillar in cancer therapy alongside surgery, chemotherapy and notably radiotherapy. There is emerging evidence to suggest both radioresistance and reduced efficacy of immune checkpoint blockade (ICB) are potentiated by the tumour microenvironment (TME) and in fact modulating aspects of this immunosuppressive milieu is instrumental to unlocking anti-tumour immunity.

The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment.

The tumour microenvironment is of critical importance in cancer development and progression and includes the surrounding stromal and immune cells, extracellular matrix, and the milieu of metabolites and signalling molecules in the intercellular space. To support sustained mitotic activity cancer cells must reconfigure their metabolic phenotype. Lactate is the major by-product of such metabolic alterations and consequently, accumulates in the tumour.

Cellular immunotherapies for cancer.

Cancer is a major burden on the healthcare system, and new therapies are needed. Recently, the development of immunotherapies, which aim to boost or use the immune system, or its constituents, as a tool to fight malignant cells, has provided a major new tool in the arsenal of clinicians and has revolutionized the treatment of many cancers.Cellular immunotherapies are based on the administration of living cells to patients and have developed hugely, especially since 2010 when Sipuleucel-T (Provenge), a DC vaccine, was the first cellular immunotherapy to be approved by the FDA.