Tumor-associated macrophages (TAMs) are predominantly M2 phenotype in solid cancers including hepatocellular carcinoma (HCC). Though differentiation of M2 macrophages has been recently linked to fatty acid oxidation (FAO), whether FAO plays a role in functional maintenance of M2 macrophages is still unclear. Here, we used an in vitro model to mimic TAM-HCC interaction in tumor microenvironment. We found that M2 monocyte-derived macrophages (MDMs) enhanced the proliferation, migration, and invasion of HCC cells through an FAO-dependent way. Further investigations identified that IL-1β mediated the pro-migratory effect of M2 MDM. Using etomoxir and siRNA to inhibit FAO and palmitate to enhance FAO, we showed that FAO was responsible for the up-regulated secretion of IL-1β and, thus, the pro-migratory effect in M2 MDMs. In addition, we proved that IL-1β induction was reactive oxygen species and NLRP3-dependent. Our study demonstrates that FAO plays a key role in functional human M2 macrophages by enhancing IL-1β secretion to promote HCC cell migration. These findings provide evidence for different dependency of energy sources in macrophages with distinct phenotypes and functions, and suggest a novel strategy to treat HCC by reprogramming cell metabolism or modulating tumor microenvironment.
Immunotherapy is a promising new therapeutic field that has demonstrated significant benefits in many solid-tumor malignancies, such as metastatic melanoma and non-small cell lung cancer. However, only a subset of these patients responds to treatment. Glioblastoma (GBM) is the most common malignant primary brain tumor with a poor prognosis of 14.6 months and few treatment advancements over the last 10 years. There are many clinical trials testing immune therapies in GBM, but patient responses in these studies have been highly variable and a definitive benefit has yet to be identified. Biomarkers are used to quantify normal physiology and physiological response to therapies. When extensively characterized and vigorously validated, they have the potential to delineate responders from non-responders for patients treated with immunotherapy in malignancies outside of the central nervous system (CNS) as well as GBM. Due to the challenges of current modalities of radiographic diagnosis and disease monitoring, identification of new predictive and prognostic biomarkers to gauge response to immune therapy for patients with GBM will be critical in the precise treatment of this highly heterogenous disease. This review will explore the current and future strategies for the identification of potential biomarkers in the field of immunotherapy for GBM, as well as highlight major challenges of adapting immune therapy for CNS malignancies.
Preclinical models that reliably recapitulate the immunosuppressive properties of human gliomas are essential to assess immune-based therapies. GL261 murine glioma cells are widely used as a syngeneic animal model of glioma, however, it has become common practice to transfect these cells with luciferase for fluorescent tumor tracking. The aim of this study was to compare the survival of mice injected with fluorescent or non-fluorescent GL261 cells and characterize the differences in their tumor microenvironment. Mice were intracranially implanted with GL261, GL261 Red-FLuc or GL261-Luc2 cells at varying doses. Cytokine profiles were evaluated by proteome microarray and Kaplan-Meier survival analysis was used to determine survival differences. Median survival for mice implanted with 5 × 10 4 GL261 cells was 18 to 21 days. The GL261 Red-FLuc implanted mice cells did not reach median survival at any tumor dose. Mice injected with 3 × 10 5 GL261-Luc2 cells reached median survival at 23 days. However, median survival was significantly prolonged to 37 days in mice implanted with 5 × 10 4 GL261-Luc2 cells. Additionally, proteomic analyses revealed significantly elevated inflammatory cytokines in the supernatants of the GL261 Red-FLuc cells and GL261-Luc2 cells. Our data suggest that GL261 Red-FLuc and GL261-Luc2 murine models elicit an anti-tumor immune response by increasing pro-inflammatory modulators. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults 1. Despite ongoing studies and numerous clinical trials, the prognosis remains poor 2. There is an urgent need to provide these patients with new therapies, as the standard of care treatment has gone unchanged for more than a decade 3. In light of the promising advances made in the area of immune therapy as a treatment for various solid cancers 4-7 , the field of neuro-oncology has embraced immunotherapies for gliomas as a promising area of preclinical and clinical investigation 8. However, recent trials like the Phase III CheckMate-143 9 and Phase III CheckMate-498 10 show poor efficacy despite promising results from pre-clinical studies 11-15. The lack of translation from preclinical to clinical studies illustrates the need for a more rigorous characterization of the pre-clinical models currently being used in the scientific community. The development of novel immune therapeutics is not possible without a reliable preclinical animal model that accurately mimics the complex immune landscape of GBM. Of the various classes of preclinical mouse models, syngeneic models have been indispensable for evaluating immune therapies in GBM 16. Syngeneic murine models are models that rely on allografts of immortalized cancer cells from the same mouse strain from which the model originates.
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