Pascual, G. | Search bioRxiv

bioRxiv2026

NGFR-driven suppression of antigen presentation limits CD8+ T cell immunity and response to checkpoint blockade

Immune checkpoint blockade has revolutionized cancer therapy; however, numerous tumors remain resistant by adopting cellular states that impede immune recognition. In this study, we identify the nerve growth factor receptor (NGFR) as a regulator of immune evasion in head and neck squamous cell carcinoma (HNSCC). Genetic ablation of Ngfr resulted in impaired tumor growth in immunocompetent MOC2 HNSCC, while pharmacological inhibition with THX-B reduced primary tumor growth and spontaneous metastatic dissemination. Single-cell profiling of MOC2 tumors demonstrated that Ngfr loss redirected tumor cells away from invasive EMT-like states and enhanced antigen-processing and presentation programs. This was accompanied by increased presentation of tumor antigens and expansion of effector CD8+ T-cells in vivo. Functionally, CD8+ T-cell depletion, Batf3 deficiency, and JAK1/2 inhibition restored the growth of Ngfr-deficient tumors, indicating that NGFR loss exposes tumors to CD8+ T-cell-mediated control through a JAK-associated antigen-presentation program. Notably, NGFR blockade sensitized otherwise resistant MOC2 tumors to anti-PD1 therapy, and the combination of THX-B with anti-PD1 significantly improved tumor control and survival. In human HNSCC, spatial profiling revealed that NGFR+ tumor regions exhibited reduced HLA-DR expression and limited CD3+ T-cell infiltration. Notably, an NGFR-associated antigen-presentation signature stratified survival and response in HNSCC patients undergoing immune checkpoint blockade. Interestingly, this signature was also linked to improved outcomes in melanoma patients. We also observed a significant increase in the effector CD8+ T-cell fraction in melanoma NGFR KO tumors linked to a significant decrease in tumor growth. These findings position NGFR as a regulator of tumor immune visibility and support NGFR inhibition as a strategy to enhance immunotherapy response.

cancer biology↗

bioRxiv2026

IFNγ at the crossroads of systemic protection and brain vulnerability to coronavirus infection

The COVID-19 pandemic, together with previous outbreaks caused by highly pathogenic coronaviruses, highlighted the importance of understanding the host determinants that influence pathogenesis, both to improve our understanding of disease mechanisms, and to strengthen preparedness for future outbreaks. In our previous work we demonstrated dysregulation of IFN{gamma} response genes in COVID-19 patients, associated with both age and viral burden, positioning IFN{gamma} as a key mediator of host defense against SARS-CoV-2. Here, we used a preclinical murine model of coronavirus infection based on murine hepatitis virus (MHV-A59), widely validated for studying SARS-CoV-2 pathogenesis, together with IFN{gamma} knockout (IFN{gamma}-KO) mice to investigate the role of this cytokine during infection. We performed a comprehensive morphological, biochemical, hematological and proteomic characterization of infected wild-type (WT) and IFN{gamma}-deficient mice. Plasma proteomics revealed impaired inflammatory and coagulation-related responses in IFN{gamma}-KO animals compared to WT controls. We found increased viral load and infectious particles in peripheral organs, including liver, spleen, heart and muscle in IFN{gamma}-KO mice, whereas these were significantly reduced in the brain. Region-specific analysis further demonstrated decreased viral load in the prefrontal cortex and hippocampus of IFN{gamma}-KO animals. Consistently, bioinformatics analysis of transcriptomics data of IFN{gamma}-treated primary neuron cultures, together with frontal cortex from human COVID-19 patients, revealed activation of neuroinflammatory and neurological disease-associated pathways, supporting a role for IFN{gamma} in driving brain inflammatory responses during coronavirus infection. Together, these findings reveal a dual role for IFN{gamma} during coronavirus infection: it is important for controlling systemic viral dissemination and limiting peripheral tissue damage, yet it may also promote viral susceptibility and exacerbated inflammatory responses in the brain. These results support IFN{gamma} modulation as a potential therapeutic strategy to prevent or mitigate neurological complications associated with COVID-19. Author SummaryViral infections are controlled by the immune system, but the same responses that protect the body can sometimes contribute to tissue damage and disease. We investigated how a key immune molecule, called Interferon Gamma, influences the outcome of Coronavirus infection in different parts of the body. Using a mouse model of Coronavirus infection with Interferon Gamma deficiency, we found that this molecule plays two opposing roles: it helps control the spread of the virus throughout the body, but it also increases vulnerability of the brain to infection and inflammation. When this immune signal was absent, animals showed higher amounts of virus in several peripheral organs but surprisingly had lower levels of virus in specific brain regions. We further found that this immune response was associated with changes in inflammation and neurological processes in human data. Our findings reveal that antiviral immunity is not always uniformly protective and that its effects depend on the tissue involved. Understanding this balance may help guide future approaches to reduce virus-associated complications while preserving the protective functions of the immune response.

microbiology↗

bioRxiv2018

Common antigenic motif recognized by human VH5-51/VL4-1 tau antibodies with distinct functionalities

Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimers Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH5-51/VL4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of VH5-51 and VL4-1 recognizes a common Pro-Xn-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.

neuroscience↗