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Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, ion and water balance, the plasticity of neurotransmitters and synapses, cerebral blood flow, and are important immune cells. During disease astrocytes become reactive and hypertrophic, a response that was long considered to be pathogenic. However, recent studies reveal that astrocytes also have a strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function and synaptic transmission little is known about the cross-talk between astrocytes and oligodendrocytes, the myelinating cells of the CNS. This communication occurs via direct cell-cell contact as well as via secreted cytokines, chemokines, exosomes, and signalling molecules. Additionally, this cross-talk is important for glial development, triggering disease onset and progression, as well as stimulating regeneration and repair. Its critical role in homeostasis is most evident when this communication fails. Here, we review emerging evidence of astrocyte-oligodendrocyte communication in health and disease. Understanding the pathways involved in this cross-talk will reveal important insights into the pathogenesis and treatment of CNS diseases.

Cancer is caused by an accumulation of somatic mutations and copy number alterations (CNAs). Besides mutations, these copy number changes are key characteristics of cancer development. Nonetheless, some tumors show hardly any CNAs, a remarkable phenomenon in oncogenesis. Head and neck squamous cell carcinomas (HNSCCs) arise by either exposure to carcinogens, or infection with the human papillomavirus (HPV). HPV-negative HNSCCs are generally characterized by many CNAs and frequent mutations in CDKN2A , TP53 , FAT1, and NOTCH1 . Here, we present the hallmarks of the distinct subgroup of HPV-negative HNSCC with no or few CNAs (CNA-quiet) by genetic profiling of 802 oral cavity squamous cell carcinomas (OCSCCs). In total, 73 OCSCC (9.1%) are classified as CNA-quiet and 729 as CNA-other. The CNA-quiet group is characterized by wild-type TP53 , frequent CASP8 and HRAS mutations, and a less immunosuppressed tumor immune microenvironment with lower density of regulatory T cells. Patients with CNA-quiet OCSCC are older, more often women, less frequently current smokers, and have a better 5-year overall survival compared to CNA-other OCSCC. This study demonstrates that CNA-quiet OCSCC should be considered as a distinct, clinically relevant subclass. Given the clinical characteristics, the patient group with these tumors will rapidly increase in the aging population. HPV-negative head and neck squamous cell carcinomas (HNSCCs) are generally characterized by many copy number alterations (CNAs) and mutations. Here, the authors characterize a subgroup of HPV-negative HNSCC with no or few CNAs (CNA-quiet) by genomic profiling of 802 oral cavity squamous cell carcinomas.

Activated microglia and macrophages play a key role in driving demyelination during multiple sclerosis (MS), but the factors responsible for their activation remain poorly understood. Here, we present evidence for a dual-trigger role of IFN-γ and alpha B-crystallin (HSPB5) in this context. In MS-affected brain tissue, accumulation of the molecular chaperone HSPB5 by stressed oligodendrocytes is a frequent event. We have shown before that this triggers a TLR2-mediated protective response in surrounding microglia, the molecular signature of which is widespread in normal-appearing brain tissue during MS. Here, we show that IFN-γ, which can be released by infiltrated T cells, changes the protective response of microglia and macrophages to HSPB5 into a robust pro-inflammatory classical response. Exposure of cultured microglia and macrophages to IFN-γ abrogated subsequent IL-10 induction by HSPB5, and strongly promoted HSPB5-triggered release of TNF-α, IL-6, IL-12, IL-1β and reactive oxygen and nitrogen species. In addition, high levels of CXCL9, CXCL10, CXL11, several guanylate-binding proteins and the ubiquitin-like protein FAT10 were induced by combined activation with IFN-γ and HSPB5. As immunohistochemical markers for microglia and macrophages exposed to both IFN-γ and HSPB5, these latter factors were found to be selectively expressed in inflammatory infiltrates in areas of demyelination during MS. In contrast, they were absent from activated microglia in normal-appearing brain tissue. Together, our data suggest that inflammatory demyelination during MS is selectively associated with IFN-γ-induced re-programming of an otherwise protective response of microglia and macrophages to the endogenous TLR2 agonist HSPB5.

BackgroundApproximately 50% of head and neck squamous cell carcinomas (HNSCC) recur after treatment with curative intent. Immune checkpoint inhibitors are treatment options for recurrent/metastatic HNSCC; however, less than 20% of patients respond. To increase this response rate, it is fundamental to increase our understanding of the spatial tumor immune microenvironment (TIME).MethodsIn total, 53 HNSCC specimens were included. Using a seven-color multiplex immunohistochemistry panel we identified tumor cells, CD163+macrophages, B cells, CD8+T cells, CD4+T helper cells and regulatory T cells (Tregs) in treatment-naive surgical resection specimens (n=29) and biopsies (n=18). To further characterize tumor-infiltrating CD8+T cells, we stained surgical resection specimens (n=12) with a five-color tumor-resident panel including CD103, Ki67, CD8 and pan-cytokeratin. Secretome analysis was performed on matched tumor suspensions (n=11) to measure protein levels.ResultsBased on CD8+T cell infiltrates, we identified four different immunotypes: fully infiltrated, stroma-restricted, immune-excluded, and immune-desert. We found higher cytokine levels in fully infiltrated tumors compared with other immunotypes. While the highest immune infiltrates were observed in the invasive margin for all immune cells, CD163+macrophages and Tregs had the highest tendency to infiltrate the tumor center. Within the tumor center, especially B cells stayed at the tumor stroma, whereas CD163+macrophages, followed by T cells, were more often localized within tumor fields. Also, B cells were found further away from other cells and often formed aggregates while T cells and CD163+macrophages tended to be more closely located to each other. Across resection specimens from various anatomical sites within the head and neck, oral cavity tumors exhibited the highest densities of Tregs. Moreover, the distance from B cells and T cells to tumor cells was shortest in oral cavity squamous cell carcinoma (OCSCC), suggesting more interaction between lymphocytes and tumor cells. Also, the fraction of T cells within 10 µm of CD163+macrophages was lowest in OCSCC, indicating fewer myeloid/T-cell suppressive interactions in OCSCC.ConclusionsWe comprehensively described the TIME of HNSCC using a unique data set of resection specimens. We discovered that the composition, as well as the relative localization of immune cells in the TIME, differed in distinct anatomical sites of the head and neck.

Curricular reform provides new opportunities to renovate important pillars of the dentistry curriculum, such as immunology and pathology, with novel approaches that appeal to new generations of students. When redesigning a course that integrates both immunology and pathology at the level that provides dentistry students with sustainable knowledge that is useful for their entire career, several challenges must be met. The objective of the present study was to describe the considerations involved in the design phase of such a new course. First, the course should be compatible with the new view on the incorporation of more active learning and teaching methods. Practically, this means that the course design should contain fewer lectures and more seminars and tutorials, where the students have fewer contact hours and actively engage in using recently acquired knowledge within a contextual background. A mandatory session of team-based learning provides opportunities to apply knowledge in combination with academic reasoning skills, teamwork, and communication. Second, for a 4-week course, choices must be made: students will not become immunologists nor pathologists in such a short period. A governing principle for this course's design is that it should be based on understanding the basic principles of immunology and pathology. The ultimate goal for the students is to make the course immuno- logical and patho- logical , challenging them to reach a next level but clearly without oversimplification. Part of the course design should allow room for students to further study an immunological topic of their own choice, thereby contributing to their immunological curiosity and to their academic development. Third, to make it tailored to a new generation of dentists, examples from the field of dentistry are actively integrated in all aspects of the course. Finally, the era of ChatGPT provides novel opportunities to use generative artificial intelligence (AI) tools in the learning process, but it demands critical thinking of how to use it in a newly designed course. A mid-course evaluation revealed that students acknowledged that immunology and pathology were presented as an integrated course. The final course evaluation endorsed the use of these various educational methods. These methods proved to be appropriate and logical choices for reaching the learning goals of the course.

Introduction The important protective role of small heat-shock proteins (HSPs) in regulating cellular survival and migration, counteracting protein aggregation, preventing apoptosis, and regulating inflammation in the central nervous system is now well-recognized. Yet, their role in the neuroinflammatory disorder multiple sclerosis (MS) is largely undocumented. With the exception of alpha B-crystallin (HSPB5), little is known about the roles of small HSPs in disease. Results Here, we examined the expression of four small HSPs during lesion development in MS, focussing on their cellular distribution, and regional differences between white matter (WM) and grey matter (GM). It is well known that MS lesions in these areas differ markedly in their pathology, with substantially more intense blood-brain barrier damage, leukocyte infiltration and microglial activation typifying WM but not GM lesions. We analysed transcript levels and protein distribution profiles for HSPB1, HSPB6, HSPB8 and HSPB11 in MS lesions at different stages, comparing them with normal-appearing brain tissue from MS patients and non-neurological controls. During active stages of demyelination in WM, and especially the centre of chronic active MS lesions, we found significantly increased expression of HSPB1, HSPB6 and HSPB8, but not HSPB11. When induced, small HSPs were exclusively found in astrocytes but not in oligodendrocytes, microglia or neurons. Surprisingly, while the numbers of astrocytes displaying high expression of small HSPs were markedly increased in actively demyelinating lesions in WM, no such induction was observed in GM lesions. This difference was particularly obvious in leukocortical lesions covering both WM and GM areas. Conclusions Since induction of small HSPs in astrocytes is apparently a secondary response to damage, their differential expression between WM and GM likely reflects differences in mediators that accompany demyelination in either WM or GM during MS. Our findings also suggest that during MS, cortical structures fail to benefit from the protective actions of small HSPs.

BackgroundAddition of neoadjuvant immune checkpoint inhibition to standard-of-care interventions for locally advanced oral cancer could improve clinical outcome.MethodsIn this study, 16 evaluable patients with stage III/IV oral cancer were treated with one dose of 480 mg nivolumab 3 weeks prior to surgery. Primary objectives were safety, feasibility, and suitability of programmed death receptor ligand-1 positron emission tomography (PD-L1 PET) as a biomarker for response. Imaging included 18F-BMS-986192 (PD-L1) PET and 18F-fluorodeoxyglucose (FDG) PET before and after nivolumab treatment. Secondary objectives included clinical and pathological response, and immune profiling of peripheral blood mononuclear cells (PBMCs) for response prediction. Baseline tumor biopsies and postnivolumab resection specimens were evaluated by histopathology.ResultsGrade III or higher adverse events were not observed and treatment was not delayed in relation to nivolumab administration and other study procedures. Six patients (38%) had a pathological response, of whom three (19%) had a major (≥90%) pathological response (MPR). Tumor PD-L1 PET uptake (quantified using standard uptake value) was not statistically different in patients with or without MPR (median 5.3 vs 3.4). All major responders showed a significantly postnivolumab decreased signal on FDG PET. PBMC immune phenotyping showed higher levels of CD8+ T cell activation in MPR patients, evidenced by higher baseline expression levels of PD-1, TIGIT, IFNγ and lower levels of PD-L1.ConclusionTogether these data support that neoadjuvant treatment of advanced-stage oral cancers with nivolumab was safe and induced an MPR in a promising 19% of patients. Response was associated with decreased FDG PET uptake as well as activation status of peripheral T cell populations.

BackgroundImmune Checkpoint Inhibitors (ICIs) are approved for the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) showing long-term clinical benefit in a small proportion of patients. Excitingly, ICI are now moving to first line therapy. To predict response and improve efficacy of ICIs, detailed insights into the HNSCC tumor immune microenvironment (TiME) is essential. Although cytotoxic CD8 T-cells are considered to be the effectors of immunotherapy approaches, a critical role of tumor-infiltrating B-cells (TIL-B) is gaining attention. Previous research in our group showed that high numbers of TIL-B were associated with improved patient survival in oral HNSCC (OSCC), independent of CD8 T-cell infiltration.1 A recent meta-analysis identified TIL-B as key prognostic marker in HNSCC outcome and ICI efficacy, outperforming established biomarkers like tumor mutational burden and PD-L1 combined positivity score.2 However, TIL-B phenotypes and their function within the TiME remain unclear. The aim of this study was to characterize B-cell subsets and antibody production spatially within OSCC and to identify OSCC-specific antibody responses in patient plasma samples.MethodsSeven- and nine marker panels were designed to perform multiplexed fluorescent immunohistochemistry (mfIHC) on a cohort of OSCC FFPE samples (n=120) to spatially characterize TIL-B phenotypes and IgG/IgA production. To investigate autoantibody production and identify OSCC-specific autoantibody targets, we screened plasma samples of 50 OSCC patients and 25 healthy controls on the HuProt high-density protein array platform.ResultsOur spatial analyses revealed increased infiltration of naïve and memory B cells, plasmablasts and plasma cells in TIL-Bhigh OSCC. In tumors enriched for plasmablasts, heterogeneous expression of IgG and IgA was observed. Plasmablasts were mostly present at the invasive tumor front, sometimes near tertiary lymphoid structures, but did not infiltrate the tumor fields. Seromic analysis revealed the presence of autoantibodies against tumor-associated antigens such as p53 and the MAGEA cancer/testis antigens, among others. Additionally, we observed an enrichment of autoantibodies directed against squamous cell-specific proteins, indicative of a humoral response in the TiME of OSCC. Top autoantibody hits not previously linked to OSCC, were validated at the protein level in patient tumor tissue and HNSCC-cell lines.ConclusionsWe identified a subset of OSCC tumors enriched in plasmablast populations, and identified squamous cell-associated autoantibodies. Our data support the apparent important role of B-cells in the TiME of HNSCC. These TIL-B populations and associated autoantibody profiles could serve as biomarkers of immunotherapy response and reveal novel targets for immunotherapy.Ethics ApprovalThis study was conducted in agreement with the Declaration of Helsinki and the medical ethical guidelines in the Code of Conduct for Proper Secondary Use of Human Tissue of the Dutch Federation of Biomedical Scientific Societies. For plasma sample collection written informed consent was obtained. The Institutional Review Board of VUmc approved the use of the material under protocols 2008.071 (A2016.035) and 2021-0511.ReferencesNauta IH, Nijenhuis DNLM, Ganzevles SH, Raaff PI, Kloosterman J, Bloemena E, Brakenhoff RH, Leemans CR, van de Ven R. Richness for tumor-infiltrating B-Cells in the oral cancer tumor microenvironment is a prognostic factor in early-stage disease and improves outcome in advanced-stage disease. Cancers. 2025;17:113 (p1–19).Chang TG, Spathis A, Schäffer AA, Gavrielatou N, Kuo F, Jia D, Mukherjee S, Sievers C, Economopoulou P, Anastasiou M, Moutafi M, Pal LR, Vos J, Lee AS, Lam S, Zhao K, Jiang P, Allen CT, Foukas P, Gomatou G, Altan-Bonnet G, Morris LTG, Psyrri A, Ruppin E. Tumor and blood B-cell abundance ourperforms established immune checkpoint response predisction signatures in head and neck cancer. Ann Oncol. 2024;36:309–320.

Activated microglia and macrophages play a key role in driving demyelination during multiple sclerosis (MS), but the factors responsible for their activation remain poorly understood. Here, we present evidence for a dual-trigger role of IFN-γ and alpha B-crystallin (HSPB5) in this context. In MS-affected brain tissue, accumulation of the molecular chaperone HSPB5 by stressed oligodendrocytes is a frequent event. We have shown before that this triggers a TLR2-mediated protective response in surrounding microglia, the molecular signature of which is widespread in normal-appearing brain tissue during MS. Here, we show that IFN-γ, which can be released by infiltrated T cells, changes the protective response of microglia and macrophages to HSPB5 into a robust pro-inflammatory classical response. Exposure of cultured microglia and macrophages to IFN-γ abrogated subsequent IL-10 induction by HSPB5, and strongly promoted HSPB5-triggered release of TNF-[alpha], IL-6, IL-12, IL-1[beta] and reactive oxygen and nitrogen species. In addition, high levels of CXCL9, CXCL10, CXL11, several guanylate-binding proteins and the ubiquitin-like protein FAT10 were induced by combined activation with IFN-γ and HSPB5. As immunohistochemical markers for microglia and macrophages exposed to both IFN-γ and HSPB5, these latter factors were found to be selectively expressed in inflammatory infiltrates in areas of demyelination during MS. In contrast, they were absent from activated microglia in normal-appearing brain tissue. Together, our data suggest that inflammatory demyelination during MS is selectively associated with IFN-γ-induced re-programming of an otherwise protective response of microglia and macrophages to the endogenous TLR2 agonist HSPB5.[PUBLICATION ABSTRACT]