No abstract

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate below 5%. CA19-9 is the most commonly used blood-based biomarker for PDAC in current clinical practice, despite having been shown repeatedly to be inaccurate and have poor diagnostic performance. This review aims to assess the reported diagnostic accuracy of all blood-based biomarkers investigated to date in PDAC, by directly comparing individual biomarkers and multi-biomarker panels, both containing CA19-9 and not (novel). A systematic review was conducted in accordance with PRISMA standards in July 2020. Individualised search strategies for three academic databases identified 5,885 studies between the years 1973-2020. After two rounds of screening, 250 studies were included. Data were extracted and assessed for bias. A multivariate three-level meta-analysis with subgroup moderators was run in R using AUC values as effect size. Based on this model, the pooled AUC value for all multi-biomarker panels (AUC=0.898, 95% CI:0.88-0.91) was significantly higher than all single biomarkers (AUC=0.803, 95% CI:0.78-0.83)(p<0.0001). The pooled AUC value for CA19-9 alone was significantly lower compared to the multi-biomarker panels containing CA19-9 (p<0.0001). For the novel biomarkers, the pooled AUC for single biomarkers was also significantly lower compared to multi-biomarker panels (p<0.0001). Novel biomarkers that have been repeatedly examined across the literature, such as TIMP-1, CEA and CA125, are highlighted as promising. These results suggest that CA19-9 may be best used as an addition to a panel of biomarkers rather than alone, and that multi-biomarker panels generate the most robust results in blood-based PDAC diagnosis.

Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy; however, only ~22% of patients achieve a complete response, and resistance mechanisms are poorly understood. The role of inflammation and immune cell biology in this setting is under-investigated. In this study, we profiled the inflammatory protein secretome of normal (non-cancer) (n = 8) and malignant rectal tissue (n = 12) pre- and post-radiation in human ex vivo explant models and examined the influence of these untreated and treated secretomes on dendritic cell biology (n = 8 for cancer and normal). These resultant profiles were correlated with patient clinical characteristics. Nineteen factors were secreted at significantly higher levels from the rectal cancer secretome when compared to the normal rectal secretome; Flt-1, P1GF, IFN-γ, IL-6, IL-10, CCL20, CCL26, CCL22, CCL3, CCL4, CCL17, GM-CSF, IL-12/IL-23p40, IL-17A, IL-1α, IL-17A/F, IL-1RA, TSLP and CXCL10 (p < 0.05). Radiation was found to have differential effects on normal rectal tissue and rectal cancer tissue with increased IL-15 and CCL22 secretion following radiation from normal rectal tissue explants (p < 0.05), while no significant alterations were observed in the irradiated rectal cancer tissue. Interestingly, however, the irradiated rectal cancer secretome induced the most potent effect on dendritic cell maturation via upregulation of CD80 and PD-L1. Patient’s visceral fat area correlated with secreted factors including CCL20, suggesting that obesity status may alter the tumour microenvironment (TME). These results suggest that radiation does not have a negative effect on the ability of the rectal cancer TME to induce an immune response. Understanding these responses may unveil potential therapeutic targets to enhance radiation response and mitigate normal tissue injury. Tumour irradiation in this cohort enhances innate immune responses, which may be harnessed to improve patient treatment outcome.

Chemotherapy upregulates immune checkpoint (IC) expression on the surface of tumour cells and IC-intrinsic signalling confers a survival advantage against chemotherapy in several cancer-types including oesophageal adenocarcinoma (OAC). However, the signalling pathways mediating chemotherapy-induced IC upregulation and the mechanisms employed by ICs to protect OAC cells against chemotherapy remain unknown. Longitudinal profiling revealed that FLOT-induced IC upregulation on OE33 OAC cells was sustained for up to 3 weeks post-treatment, returning to baseline upon complete tumour cell recovery. Pro-survival MEK signalling mediated FLOT-induced upregulation of PD-L1, TIM-3, LAG-3 and A2aR on OAC cells promoting a more immune-resistant phenotype. Single agent PD-1, PD-L1 and A2aR blockade decreased OAC cell viability, proliferation and mediated apoptosis. Mechanistic insights demonstrated that blockade of the PD-1 axis decreased stem-like marker ALDH and expression of DNA repair genes. Importantly, combining single agent PD-1, PD-L1 and A2aR blockade with FLOT enhanced cytotoxicity in OAC cells. These findings reveal novel mechanistic insights into the immune-independent functions of IC-intrinsic signalling in OAC cells with important clinical implications for boosting the efficacy of the first-line FLOT chemotherapy regimen in OAC in combination with ICB, to not only boost anti-tumour immunity but also to suppress IC-mediated promotion of key hallmarks of cancer that drive tumour progression.