Lung cancer is the most common cause of cancer mortality worldwide and, while tobacco smoke remains the primary cause, there is increasing concern that vaping and E-cigarette use may also increase lung cancer risk. This review concentrates on the current data, scholarship and active foci of research regarding potential cancer risk and oncogenic mechanisms of vaping and lung cancer. Materials and methods: We performed a literature review of current and historical publications on lung cancer oncogenesis, vaping device/e-liquid contents and daughter products, molecular oncogenic mechanisms and the fundamental, potentially oncogenic, effects of electronic cigarette smoke/e-liquid products. Results: E-cigarette devices and vaping fluids demonstrably contain a series of both definite and probable oncogens including nicotine derivatives (e.g. nitrosnornicotine, nitrosamine ketone), polycyclic aromatic hydrocarbons, heavy metals (including organometal compounds) and aldehydes/other complex organic compounds. These arise both as constituents of the e-liquid (with many aldehydes and other complex organics used as flavourings) and as a result of pyrolysis/complex organic reactions in the electronic cigarette device (including unequivocal carcinogens such as formaldehydeformed from pyrolysis of glycerol). Various studies demonstrate in vitro transforming and cytotoxic activity of these derivatives. E-cigarette device use has been significantly increasingparticularly amongst the younger cohort and non-smokers; thus, this is an area of significant concern for the future. Conclusion: Although research remains somewhat equivocal, there is clear reason for concern regarding the potential oncogenicity of E-Cigarettes/E-Liquids with a strong basic and molecular science basis. Given lag times (extrapolating from tobacco smoke data) of perhaps 20 years, this may have significant future public health implications. Thus, the authors feel further study in this field is strongly warranted and consideration should be made for tighter control and regulation of these products.

Lung cancer is a leading cause of cancer-related deaths, contributing to 18.4% of cancer deaths globally. Treatment of non-small cell lung carcinoma has seen rapid progression with targeted therapies tailored to specific genetic drivers. However, identifying genetic alterations can be difficult due to lack of tissue, inaccessible tumors and the risk of complications for the patient with serial tissue sampling. The liquid biopsy provides a minimally invasive method which can obtain circulating biomarkers shed from the tumor and could be a safer alternative to tissue biopsy. While tissue biopsy remains the gold standard, liquid biopsies could be very beneficial where serial sampling is required, such as monitoring disease progression or development of resistance mutations to current targeted therapies. Liquid biopsies also have a potential role in identifying patients at risk of relapse post treatment and as a component of future lung cancer screening protocols. Rapid developments have led to multiple platforms for isolating circulating tumor cells (CTCs) and detecting circulating tumor DNA (ctDNA); however, standardization is lacking, especially in lung carcinoma. Additionally, clonal hematopoiesis of uncertain clinical significance must be taken into consideration in genetic sequencing, as it introduces the potential for false positives. Various biomarkers have been investigated in liquid biopsies; however, in this review, we will concentrate on the current use of ctDNA and CTCs, focusing on the clinical relevance, current and possible future applications and limitations of each.

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Aim Visceral obesity is a key risk factor in the development of oesophagogastric junctional adenocarcinoma (OGJ), predominantly via generation of systemic low grade inflammation. Obesity-induced inflammation promotes resistance to current standards of care, enhancing tumour cell growth and survival. This study investigates the effect of the visceral adipose tissue secretome from OGJ patients with early versus advanced tumours on T-cell immunity and the role of immune checkpoint blockade in enhancing anti-tumour immunity. Methods and results Visceral adipose conditioned media (ACM) from both early and late-stage OGJ patients significantly altered T cell activation status, upregulating co-stimulatory marker CD27 on T cells. ACM from both early and late-stage OGJ patients significantly altered immune checkpoint expression profiles downregulating immune checkpoints (ICs) on the surface of dual Th1/17-like and Th17-like cells and upregulating ICs on the surface of Th1-like cells and Treg cells. ACM derived from early-stage OGJ patients but not late-stage OGJ patients increased IFN-γ production by T cells. The addition of immune checkpoint blockers (ICBs) did not increase IFN-γ production by T cells in the presence of late-stage ACM, collectively highlighting the dichotomous immunostimulatory effect of early-stage ACM and immune-inhibitory effect of late-stage ACM. Interestingly, ACM from early-stage OGJ patients was more pro-inflammatory than ACM from late-stage patients, reflected by decreased levels of IL-17A/F, TNF-α, IL-1RA and IL-5. Conclusion The ACM-induced upregulation of ICs on T cells highlights a therapeutic vulnerability that could be exploited by ICBs to harness anti-cancer immunity and improve clinical outcomes for OGJ patients. Graphical Abstract Schematic workflow – (A) visceral adipose tissue was taken from OAC patients at time of surgery and cultured for 72 h in media. (B) The harvested ACM was co-cultured with healthy donor PBMCs that were concurrently activated with anti-CD3/28 for 48 h and T cell immunophenotyping was carried out by flow cytometry. Key findings – (A) Early and late stage ACM enhanced a Th1-like phenotype and upregulated CTLA-4 on Th1-like cells. A Th17-like phenotype was also enhanced in addition with a Treg-like phenotype. CTLA-4 and PD-L1 were upregulated on the surface of Treg-like cells. (B) ICB-attenuated IL-17 production by T cells. However, ACM attenuated ICB-mediated reduction in IL-10 production by T cells. Higher levels of pro-inflammatory factors were found in early stage ACM compared with late stage ACM.

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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). Tumour-infiltrating and circulating T cells had significantly lower CD27 expression and significantly higher CD69 expression post-FLOT and post-CROSS treatment. Similarly, the supernatant from FLOT- and CROSS-treated OGJ cell lines and from FLOT- and CROSS-treated OGJ biopsies cultured ex vivo also decreased CD27 and increased CD69 expression on T cells. Following 48 h treatment with post-FLOT and post-CROSS tumour conditioned media the frequency of CD69+ T cells in culture negatively correlated with the levels of soluble immunosuppressive pro-angiogenic factors in the conditioned media from ex vivo explants. Supernatant from FLOT- and CROSS-treated OGJ cell lines also increased the cytotoxic potential of healthy donor T cells ex vivo and enhanced OGJ patient-derived lymphocyte mediated-killing of OE33 cells ex vivo. Collectively, this data demonstrate that FLOT and CROSS chemotherapy regimens possess immunostimulatory properties, identifying these chemotherapy regimens as rational synergistic partners to test in combination with immunotherapy and determine if this combinatorial approach could boost anti-tumour immunity in OGJ patients and improve clinical outcomes.