Eliana Marinari

Although obesity is a major risk factor for cancer, it may also improve the response to cancer therapy. Here we investigated the impact of obesity on the efficacy of immune checkpoint inhibitors (ICI). In male mice, obesity promoted tumor growth but enhanced the response to ICI. This was associated with higher expression of immune-related genes within the tumor and enhanced infiltration of tumor-specific CD8 ⁺ T cells. Further, obesity in mice was associated with higher estrogen levels and enrichment of estrogen response genes in the tumor, and anti–programmed cell death 1 (anti–PD-1) efficacy was reduced upon administration of the aromatase inhibitor letrozole, which blocks the production of estrogens. Mechanistically, adipocyte-derived estrogens increased antigen presentation by dendritic cells and tumor-specific CD8 ⁺ T cell cytotoxicity. Last, overweight and obese men with melanoma responded better to ICI, with high estrogen levels being associated with improved response and survival. Our results suggest that estrogens may serve as a predictive factor of response to ICI in men with melanoma.

Background: Incidence of brain metastases is precisely unknown and there is no clear consensus on their management. We aimed to determine the incidence of brain metastases among patients with genito-urinary primaries, present patients’ characteristics and identify prognostic factors. Method: We identified 51 patients treated in Geneva University Hospitals between January 1992 and December 2019. We retrospectively correlated their overall survival with 23 variables. We repeated a multivariate analysis with significant variables. Results: Overall incidence of Brain Metastases (BMs) among Genito-Urinary (GU) patients is estimated to be 1.76% (range per primary GU tumour type: 0.00–6.65%). BMs originate from germ cell tumours in two cases (3.92%), from urothelial cell carcinoma in 15 cases (29.41%), from prostate cancer in 13 cases (25.49%), and from renal cell carcinoma in 21 cases (41.18%); there are no BMs from penile cancer in our cohort. The median age at BM diagnosis is 67 years old (range: 25–92). Most patients (54%) have a stage IV disease at initial diagnosis and 11 patients (22%) have BM at initial diagnosis. Only six patients (12%) are asymptomatic at BM diagnosis. The median Overall Survival (OS) from BM diagnosis is 3 months (range: 0–127). Five patients (10%) are long survivors (OS > 24 months). OS is significantly influenced by patient performance status and administration of systemic treatment. In the absence of meningeal carcinomatosis, OS is influenced by systemic treatment and stereotactic radiosurgery. We also apply the Graded Prognostic Assessment (GPA) score to our cohort and note significant differences between groups. Conclusion: Brain metastases from solid tumours is not a uniform disease, with a prognosis varying a lot among patients. The optimal management for patients with genito-urinary malignancies with brain metastases remain unclear and further research is needed.

Objective High-grade glioma (HGG) rarely spreads outside the CNS. To test the hypothesis that the lesions were metastases originating from an HGG, we sequenced the relapsing HGG and distant extraneural lesions. Methods We performed whole-exome sequencing of an HGG lesion, its local relapse, and distant lesions in bone and lymph nodes. Results Phylogenetic reconstruction and histopathologic analysis confirmed the common glioma origin of the secondary lesions. The mutational profile revealed an IDH1/2 wild-type HGG with an activating mutation in EGFR and biallelic focal loss of CDKN2A (9p21). In the metastatic samples and the local relapse, we found an activating PIK3CA mutation, further copy number gains in chromosome 7 (EGFR), and a putative pathogenic driver mutation in a canonical splice site of FLNA. Conclusions Our findings demonstrate tumor spread outside the CNS and identify potential genetic drivers of metastatic dissemination outside the CNS, which could be leveraged as therapeutic targets or potential biomarkers.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, characterized by a high degree of intertumoral heterogeneity. However, a common feature of the GBM microenvironment is hypoxia, which can promote radio- and chemotherapy resistance, immunosuppression, angiogenesis, and stemness. We experimentally defined common GBM adaptations to physiologically relevant oxygen gradients, and we assessed their modulation by the metabolic drug metformin. We directly exposed human GBM cell lines to hypoxia (1% O₂) and to physioxia (5% O₂). We then performed transcriptional profiling and compared our in vitro findings to predicted hypoxic areas in vivo using in silico analyses. We observed a heterogenous hypoxia response, but also a common gene signature that was induced by a physiologically relevant change in oxygenation from 5% O₂ to 1% O₂. In silico analyses showed that this hypoxia signature was highly correlated with a perinecrotic localization in GBM tumors, expression of certain glycolytic and immune-related genes, and poor prognosis of GBM patients. Metformin treatment of GBM cell lines under hypoxia and physioxia reduced viable cell number, oxygen consumption rate, and partially reversed the hypoxia gene signature, supporting further exploration of targeting tumor metabolism as a treatment component for hypoxic GBM.

Immunotherapy, including therapeutic vaccines, is increasingly being developed for patients with high-grade glioma, and combinations of immunotherapies and synergy with standard of care are being investigated. In this regard, bevacizumab (BEV) has been shown to synergize with immunotherapy in preclinical studies of glioma and in other tumour entities. Here, we conducted a post-hoc exploratory study to evaluate the effect of the IMA950/poly-ICLC peptide vaccine on subsequent BEV administration in high-grade glioma patients. 16 IMA950-vaccinated and 40 non-vaccinated patients were included. At initial diagnosis, patients benefited from surgery and chemoradiation. At first or subsequent recurrence, patients received 10mg/kg of BEV every 2–3 weeks. Primary endpoints were overall survival (OS) and progression-free survival (PFS) from BEV initiation. IMA950-vaccinated patients did not show improved response to BEV as compared to non-vaccinated patients: there was no difference in median PFS (2.6 vs. 4.2 months for vaccinated and control patients, respectively, p = 0.50) nor in median OS (7.8 vs. 10.0 months for vaccinated and control patients, respectively, p = 0.69). In conclusion, potential synergy of BEV and therapeutic vaccines, when administered sequentially, has yet to be established in the clinical setting of GBM recurrence. Potential synergy of concomitant administration should be tested in future trials.