Radiotherapy, immunotherapy, and the tumour microenvironment: Turning an immunosuppressive milieu into a therapeutic opportunity.

Immune checkpoint blockade (ICB) has revolutionised the treatment of solid tumours, yet most patients do not derive a clinical benefit. Resistance to ICB is often contingent on the tumour microenvironment (TME) and modulating aspects of this immunosuppressive milieu is a goal of combination treatment approaches. Radiation has been used for over a century in the management of cancer with more than half of all cancer patients receiving radiotherapy. Here, we outline the rationale behind combining radiotherapy with ICB, a potential synergy through mutually beneficial remodelling of the TME. We discuss the pleiotropic effects radiation has on the TME including immunogenic cell death, activation of cytosolic DNA sensors, remodelling the stroma and vasculature, and paradoxical infiltration of both anti-tumour and suppressive immune cell populations. These events depend on the radiation dose and fractionation and optimising these parameters will be key to develop safe and effective combination regimens. Finally, we highlight ongoing efforts that combine radiation, immunotherapy and inhibitors of DNA damage response, which can help achieve a favourable equilibrium between the immunogenic and tolerogenic effects of radiation on the immune microenvironment.

Impact of visceral obesity and metabolic syndrome on the postoperative immune, inflammatory, and endocrine response following surgery for esophageal adenocarcinoma.

Visceral obesity and metabolic syndrome (MetSyn) represent a constellation of inflammation, insulin resistance, and hyperglycemia and are established risk factors for gastrointestinal cancer. However, their impact on the immune and inflammatory response after major upper gastrointestinal oncologic surgery is unknown. In 125 consecutive patients who underwent esophagectomy, C-reactive protein (CRP) and CRP:albumin levels were recorded preoperatively and on days 1, 3, 7, and 14 postoperatively. In a subset of 30 patients, circulating levels of IL-6, IL-8, IL-10, IL-12p70, IFN-γ, TNF-α, TGF-ß, and cortisol were measured. Incidences of postoperative complications were prospectively recorded. In the study cohort, 51% of patients were viscerally obese, 40.7% had MetSyn, and 33.6% were hyperglycemic. Viscerally obese and MetSyn-positive patients demonstrated greater postoperative CRP levels and CRP:albumin levels on day 7 and day 14 compared with nonobese and MetSyn-negative patients (P < 0.05). Higher postoperative circulating levels of cortisol were observed in the viscerally obese and hyperglycemic patients compared to nonobese and normoglycemic patients. No association was observed between visceral obesity, MetSyn or hyperglycemia, and postoperative cytokine profile. Viscerally obese patients had an increased overall incidence of postoperative complications compared to nonobese patients (67.2% vs. 47.5%, P = 0.031) on univariate but not multivariate analysis (P = 0.078) and visceral obesity was not associated with an increased incidence of specific complications. Visceral obesity, MetSyn, and hyperglycemia are prevalent in patients undergoing major upper gastrointestinal resection and are associated with an exaggerated acute-phase inflammatory response postoperatively. Further research is warranted to determine whether this association is directly causal.

The esophagitis to adenocarcinoma sequence; the role of inflammation.

Esophageal adenocarcinoma (EAC) is the eighth most common cancer worldwide, and approximately 15% of patients survive 5years. Reflux disease (GERD) and Barrett's esophagus (BE) are major risk factors for the development of EAC, and epidemiologic studies highlight a strong association with obesity. The immune, inflammatory and intracellular signaling changes resulting from chronic inflammation of the esophageal squamous epithelium are increasingly well characterized. In GERD and Barrett's, an essential role for T-cells in the initiation of inflammation in the esophagus has been identified, and a balance between T-cell responses and phenotype may play an important role in disease progression. Obesity is a chronic low-grade inflammatory state, fueled by adipose tissue derived- inflammatory mediators such as IL-6, TNF-α and leptin, representing a novel area for targeted research. Additionally, reactive oxygen species (ROS) and receptor tyrosine kinase (RTK) activation may drive progression from esophagitis to EAC, and downstream signaling pathways employed by these molecules may be important. This review will explain the diverse range of mechanisms potentially driving and maintaining inflammation within the esophagus and explore both existing and future therapeutic strategies targeting the process.

The SGBS cell strain as a model for the in vitro study of obesity and cancer

INTRODUCTION: The murine adipocyte cell line 3T3-L1 is well characterised and used widely, while the human pre-adipocyte cell strain, Simpson-Golabi-Behmel Syndrome (SGBS), requires validation for use in human studies. Obesity is currently estimated to account for up to 41 % of the worldwide cancer burden. A human in vitro model system is required to elucidate the molecular mechanisms for this poorly understood association. This work investigates the relevance of the SGBS cell strain for obesity and cancer research in humans. MATERIALS AND METHODS: Pre-adipocyte 3T3-L1 and SGBS were differentiated according to standard protocols. Morphology was assessed by Oil Red O staining. Adipocyte-specific gene expression was measured by qPCR and biochemical function was assessed by glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity. Differential gene expression in oesophageal adenocarcinoma cell line OE33 following co-culture with SGBS or primary omental human adipocytes was investigated using Human Cancer Profiler qPCR arrays. RESULTS: During the process of differentiation, SGBS expressed higher levels of adipocyte-specific transcripts and fully differentiated SGBS expressed more similar morphology, transcript levels and biochemical function to primary omental adipocytes, relative to 3T3-L1. Co-culture with SGBS or primary omental adipocytes induced differential expression of genes involved in adhesion (ITGB3), angiogenesis (IGF1, TEK, TNF, VEGFA), apoptosis (GZMA, TERT) and invasion and metastasis (MMP9, TIMP3) in OE33 tumour cells. CONCLUSIONS: Comparable adipocyte-specific gene expression, biochemical function and a shared induced gene signature in co-cultured OE33 cells indicate that SGBS is a relevant in vitro model for obesity and cancer research in humans (AU)

Role of the insulin-like growth factor 1 axis and visceral adiposity in oesophageal adenocarcinoma.

BACKGROUND: Epidemiological studies have linked obesity with many cancers. The insulin-like growth factor (IGF) 1 axis may be an important mediator in obesity-associated cancer. This study examined the relationship between IGF-1 and its receptor (IGF-1R) in oesophageal adenocarcinoma, a cancer strongly linked to obesity. METHODS: Patients with oesophageal adenocarcinoma considered suitable for attempted curative treatment were studied. Visceral adiposity was defined by waist circumference or visceral fat area. Free and total IGF-1 in serum were measured by enzyme-linked immunosorbent assay. Quantitative polymerase chain resection was used to determine mRNA expression of IGF-1 and IGF-1R in resected tumour samples. IGF-1R expression in tissue microarrays (TMAs) was quantified by immunohistochemistry. RESULTS: A total of 220 patients were studied. Total and free IGF-1 levels were significantly increased in the serum of viscerally obese patients. Gene expression analysis revealed a significant association between obesity status and both IGF-1R (P = 0·021) and IGF-1 (P = 0·031) in tumours. TMA analysis demonstrated that IGF-1R expression in resected tumours was significantly higher in viscerally obese patients than in those of normal weight (P = 0·023). Disease-specific survival was longer in patients with negative IGF-1R expression than in those with IGF-1R-positive tumours (median 60·0 versus 23·4 months; P = 0·027). CONCLUSION: This study highlighted the association of the IGF axis with visceral obesity, and a potential impact on the biology of oesophageal adenocarcinoma through its receptor. Targeting the IGF axis may have a rationale in future studies.

Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue.

Obesity has been associated with increased incidence and mortality of oesophageal and colorectal adenocarcinoma. Excess central adiposity may drive this association through an altered inflammatory milieu. Utilising a unique adipose tissue bioresource we aimed to determine the pro-tumour properties of visceral adipose tissue. Comparing subcutaneous and visceral adipose tissue depots, we observed significantly higher levels of VEGF and IL-6, along with significantly higher proportions of CD8(+) T cells and NKT cells in visceral adipose tissue. Significantly higher levels of VEGF were observed in the conditioned media from visceral adipose tissue of centrally obese compared to non-obese patients. We also report a significant increase in oesophageal and colorectal tumour cell proliferation following culture with conditioned media from visceral adipose tissue of centrally obese patients. Neutralising VEGF in the conditioned media significantly decreased tumour cell proliferation. This novel report highlights a potential mechanism whereby visceral adipose tissue from centrally obese cancer patients may drive tumour progression.

T lymphocyte activation in visceral adipose tissue of patients with oesophageal adenocarcinoma.

BACKGROUND: Visceral adipose tissue may fuel obesity-associated chronic inflammation and tumorigenesis. T cells may be important in visceral adipose tissue in driving inflammation, but they have not yet been characterized in patients with cancer. This study aimed to characterize T lymphocytes in visceral adipose tissue and peripheral blood from patients with oesophageal adenocarcinoma. METHODS: Omental fat was taken from 35 patients with oesophageal adenocarcinoma at the start of surgery. Flow cytometry was performed to assess T cell activation status and cytokine production in omentum and peripheral blood. RESULTS: A large population of lymphocytes was present in the omentum. Omental CD4(+) and CD8(+) T cells displayed significantly enhanced expression of the T cell activation markers CD69 (P < 0·001) and CD107a (CD8(+) T cells: P < 0·01), and significantly decreased CD62L expression (P < 0·05), compared with blood. Significantly higher proportions of CD45RO(+) T cells compared with CD45RA(+) T cells were present in omentum (P < 0·001 and P = 0·012 for CD4(+) and CD8(+) cells respectively). Interferon γ was the most abundant cytokine expressed by omental T cells, with a significantly higher level than in blood and subcutaneous adipose tissue (P < 0·01). CONCLUSION: Visceral adipose tissue is a rich source of activated proinflammatory CD4(+) and CD8(+) T cells. It may fuel chronic inflammation via T cell-mediated pathways.

Obesity and gastrointestinal cancer.

BACKGROUND: There is emerging evidence of a strong association between obesity and gastrointestinal cancer. This review summarizes the evidence from an epidemiological and pathophysiological perspective. METHODS: Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles were identified. Selection of articles was based on peer review, journal and relevance. RESULTS: Numerous epidemiological studies consistently identified an increased risk of developing oesophageal adenocarcinoma and colorectal carcinoma in the obese. The association between obesity and other gastrointestinal malignancies was less robust. Sex seems important with respect to cancer risk. Adipose tissue, particularly viscerally located fat, is metabolically active and exerts systemic endocrine effects. Putative pathophysiological mechanisms linking obesity and carcinogenesis include the insulin-like growth factor axis, adipocytokines and sex steroids. CONCLUSION: A better understanding of the mechanisms that link obesity and cancer may uncover targets for intervention. Tackling obesity may result in a reduction in the incidence in addition to mortality of certain cancers in future.

Obesity and post-operative complications in patients undergoing non-bariatric surgery.

As the prevalence of obesity continues to rise in society, an increasing number of patients undergoing non-bariatric surgery will be obese. Obesity is known to increase morbidity and mortality in the general population and thus is perceived as a risk factor for adverse post-surgical outcomes. This association is not clear-cut, however, and there is a lack of consensus in the literature on the risk between obesity and specific complications, in particular relating to infection, wound healing, respiratory and venous thromboembolism. The paucity of studies, as well as a lack of consistency of definition of obesity, with an over-reliance on body mass index rather than body composition analysis, may underlie this confusion. Emerging concepts position central/visceral adipose tissue as potentially key to the pathogenesis of the comorbidities associated with obesity, thus this article reviews emerging research investigating the association between visceral obesity, the metabolic syndrome and resulting post-operative complications. It is hypothesized that the state of chronic inflammation and dysmetabolism observed in visceral obese patients negatively influences post-operative outcomes and represents a potential target for pharmaconutrition. The need for further research investigating the influence of visceral adiposity on immune function post surgery and its impact on post-operative morbidity and mortality is highlighted.