Highlights d Gut alterations are related to impaired sociability in alcohol use disorder patients d Human-to-mice microbiota transplantation reproduces metabolic and behavioral disorders d Microbial ethanol production is linked to reduced b-hydroxybutyrate (BHB) synthesis d In mice and humans, BHB level is associated with depression and social impairments

Head and neck squamous cell carcinomas (HNSCC) are one of the most prevalent cancers worldwide. Active human papillomavirus (HPV) infection has been identified as an important additional risk factor and seems to be associated with a better prognosis in non-drinker and non-smoker young patients with oropharyngeal SCC. The better response of the immune system against the HPV-induced HNSCC is suspected as a potential explanation for the better prognosis of young patients. To further assess this hypothesis, our review aims to shed light the current knowledge about the impact of HPV infection on the immune response in the context of HNSCC, focusing on the innate immune system, particularly highlighting the role of macrophages, Langerhans and myeloid cells, and on the adaptative immune system, pointing out the involvement of T regulatory, T CD8 and T CD4 lymphocytes. In addition, we also review the preventive (HPV vaccines) and therapeutic (checkpoint inhibitors) strategies against HPV-related HNSCC, stressing the use of anti-CTLA4, PD-L1, PD-L2 antibodies alone and in combination with other agents able to modulate immune responses.

Functionalized iron oxide nanoparticles (IONPs) are increasingly being designed as a theranostic nanoplatform combining specific targeting, diagnosis by magnetic resonance imaging (MRI), and multimodal therapy by hyperthermia. The effect of the size and the shape of IONPs is of tremendous importance to develop theranostic nanoobjects displaying efficient MRI contrast agents and hyperthermia agent via the combination of magnetic hyperthermia (MH) and/or photothermia (PTT). Another key parameter is that the amount of accumulation of IONPs in cancerous cells is sufficiently high, which often requires the grafting of specific targeting ligands (TLs). Herein, IONPs with nanoplate and nanocube shapes, which are promising to combine magnetic hyperthermia (MH) and photothermia (PTT), were synthesized by the thermal decomposition method and coated with a designed dendron molecule to ensure their biocompatibility and colloidal stability in suspension. Then, the efficiency of these dendronized IONPs as contrast agents (CAs) for MRI and their ability to heat via MH or PTT were investigated. The 22 nm nanospheres and the 19 nm nanocubes presented the most promising theranostic properties (respectively, r2 = 416 s−1·mM−1, SARMH = 580 W·g−1, SARPTT = 800 W·g−1; and r2 = 407 s−1·mM−1, SARMH = 899 W·g−1, SARPTT = 300 W·g−1). MH experiments have proven that the heating power mainly originates from Brownian relaxation and that SAR values can remain high if IONPs are prealigned with a magnet. This raises hope that heating will maintain efficient even in a confined environment, such as in cells or in tumors. Preliminary in vitro MH and PTT experiments have shown the promising effect of the cubic shaped IONPs, even though the experiments should be repeated with an improved set-up. Finally, the grafting of a specific peptide (P22) as a TL for head and neck cancers (HNCs) has shown the positive impact of the TL to enhance IONP accumulation in cells.

We assessed immune cell infiltrates to develop an immunoscore for prognosis and to investigate its correlation with the clinical data of patients with head and neck cancer. CD8, FoxP3, and CD68 markers were evaluated by immunohistochemistry in 258 carcinoma samples and positive cells were counted in stromal and intra-tumoral compartments. The RStudio software was used to assess optimal cut-offs to divide the population according to survival while the prognostic value was established by using Kaplan–Meier curves and Cox regression models for each immune marker alone and in combination. We found with univariate analysis that the infiltration of immune cells in both compartments was predictive for recurrence-free survival and overall survival. Multivariate analysis revealed that CD8+ density was an independent prognostic marker. Additionally, the combination of CD8, FoxP3, and CD68 in an immunoscore provided a significant association with overall survival (p = 0.002, HR = 9.87). Such an immunoscore stayed significant (p = 0.018, HR = 11.17) in a multivariate analysis in comparison to tumor stage and histological grade, which had lower prognostic values. Altogether, our analysis indicated that CD8, FoxP3, and CD68 immunoscore was a strong, independent, and significant prognostic marker that could be introduced into the landscape of current tools to improve the clinical management of head and neck cancer patients.

The head and neck tumor microenvironment (TME) is highly infiltrated with macrophages. More specifically, tumor-associated macrophages (TAM/M2-like) are one of the most critical components associated with poor overall survival in head and neck cancers (HNC). Two extreme states of macrophage phenotypes are described as conducting pro-inflammatory/anti-tumoral (M1) or anti-inflammatory/pro-tumoral (M2) activities. Moreover, specific metabolic pathways as well as oxidative stress responses are tightly associated with their phenotypes and functions. Hence, due to their plasticity, targeting M2 macrophages to repolarize in the M1 phenotype would be a promising cancer treatment. In this context, we evaluated macrophage infiltration in 60 HNC patients and demonstrated the high infiltration of CD68+ cells that were mainly related to CD163+ M2 macrophages. We then optimized a polarization protocol from THP1 monocytes, validated by specific gene and protein expression levels. In addition, specific actors of glutamine pathway and oxidative stress were quantified to indicate the use of glutaminolysis by M2 and the production of reactive oxygen species by M1. Finally, we evaluated and confirmed the plasticity of our model using M1 activators to repolarize M2 in M1. Overall, our study provides a complete reversible polarization protocol allowing us to further evaluate various reprogramming effectors targeting glutaminolysis and/or oxidative stress in macrophages.