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Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent epidemiological studies have shown that obesity, typically measured by increased body mass index (BMI), is associated with an increased risk of gastroesophageal adenocarcinoma (GEAC), but the contributing molecular and immune mechanisms remain unknown. Since obesity is known to promote chronic inflammation, we hypothesized that obesity leads to inflammation-related immune dysfunction, which can be reversed by immune-modulating therapy. To test our hypothesis, we examined the clinical and molecular data from advanced GEAC patients. To this end, 46 GEAC tumors were evaluated for biomarkers representing tumor inflammation, cell proliferation, and PD-L1 expression. A CoxPH regression model with potential co-variates, followed by pairwise post hoc analysis, revealed that inflammation in the GEAC tumor microenvironment is associated with improved overall survival, regardless of BMI. We also observed a significant association between cell proliferation and progression-free survival in overweight individuals who received immune-modulating therapy. In conclusion, our data confirm the role of the immune system in the natural course of GEAC and its responses to immunotherapies, but do not support the role of BMI as an independent clinically relevant biomarker in this group of patients. [ABSTRACT FROM AUTHOR]