InVivoPlus mouse IgG1 isotype control, unknown specificity

Cancer cells adopt multiple strategies to avoid detection and destruction by the immune system, including exploiting immune checkpoint pathways. B7x (B7-H4, B7S1, or VTCN1), a member of the B7/CD28 family, is frequently expressed in advanced bladder cancer, yet its role in bladder cancer progression and resistance to therapy remains poorly understood. Resistance to PD-1/PD-L1 immune checkpoint blockade immunotherapy significantly limits durable responses, with only 20%-25% of patients with muscle-invasive bladder cancer (MIBC) achieving long-term benefits. Here, we demonstrated that B7x mRNA and protein expression were associated with poor survival outcomes in MIBC patients and mouse models of bladder cancer, respectively. Stable expression of B7x in immune-competent bladder cancer mouse models resulted in enhanced tumor growth and splenomegaly, driven by the exclusion and suppression of tumor-infiltrating antitumor immune cells and the enrichment of pro-tumor and immunosuppressive cells. Consistently, in the IMvigor210 clinical trial, high B7x mRNA expression was correlated with poorer survival in MIBC patients treated with PD-L1 blockade. Notably, combination therapy targeting B7x alongside PD-1/PD-L1 or CTLA-4 blockade reduced tumor burden and overcame resistance to monotherapy. These findings establish B7x as a substantial driver of immune evasion in bladder cancer and highlight its potential as a therapeutic target to improve immune checkpoint blockade efficacy in MIBC.

Maternal infections during gestation cause perturbed neuroimmune interactions and increased risk of neurodevelopmental disorders in the offspring. Using a maternal immune activation model with polyinosinic:polycytidylic acid (poly(I:C)), we investigated how maternal infections reshape the progeny hippocampal landscape. Poly(I:C) increased maternal type I interferon (IFN-I), disrupting neuronal transcriptional trajectories and excitatory synapse homeostasis in juvenile offspring. Poly(I:C) offspring microglia exhibited reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of synapse elimination and brain development, accompanied by impaired phagocytosis and suppressed IFN-I-responsive substate. Consistently, a blunted IFN-I signature was observed in postmortem tissues from schizophrenic patients. TREM2 deficiency was associated with aberrant maternal IFN-I and altered neuronal and microglial signatures in poly(I:C) offspring, highlighting its regulatory role in neurodevelopmental pathologies. Blocking maternal IFN-I signaling restored synaptic defects and TREM2 function, suggesting that monitoring IFN-I responses during pregnancy and targeting defective IFN-I cascades in the newborn may represent viable therapeutic approaches to mitigate neurodevelopmental dysfunctions.

Although pancreatic cancer is generally refractory to immune checkpoint blockade, recent studies of tumor-infiltrating T cells in human tumor samples demonstrated the presence of in vivo expanded, tumor-reactive T cell receptor (TCR) clonotypes. Here, we explored the T cell repertoire in a murine pancreatic cancer model by combining single-cell transcriptomics with functional TCR characterization. This uncovered a substantial diversity of tumor-reactive TCR clonotypes. Whereas some of these were exclusively reactive against the autologous tumor, most TCRs reacted against syngeneic tumor cells of diverse tissue origin. Immunopeptidome analyses revealed three T cell epitopes reflecting distinct tumor antigen classes also found in human cancers: a mutanome-encoded neoantigen, an epitope encoded by an ectopically expressed endogenous retroviral provirus, and an epitope derived from a cell stress-induced autoantigen. These findings underline the importance of uncovering the antigen specificity of the natural tumor-reactive TCR repertoire to assess its therapeutic potential and safety with regard to personalized immunotherapy.

The stromal cell compartment plays a central part in the maintenance of tissue homeostasis by coordinating with the immune system throughout inception, amplification and resolution of inflammation1. Chronic inflammation can impede the phased regulation of tissue restitution, resulting in the scarring complication of fibrosis. In inflammatory bowel disease, stromal fibroblasts have been implicated in treatment-refractory disease and fibrosis2,3; however, their mechanisms of activation have remained undefined. Through integrative single-cell and spatial profiling of intestinal tissues from patients with inflammatory bowel disease, we uncovered a pathological cell nexus centred on inflammation-associated fibroblasts. These fibroblasts were induced by proinflammatory macrophages (FCN1+IL1B+) and, in turn, produced profibrotic cytokine IL-11. We investigated the inflammation-associated fibroblast activation program at a mechanistic level using genome-wide CRISPR knockout and activation screens and identified the transcription factor GLIS3 as a key regulator of a gene regulatory network governing expression of inflammatory and fibrotic genes. We further demonstrated that the magnitude of the GLIS3 gene expression program in intestinal biopsies could be used to stratify patients with ulcerative colitis by disease severity, and that fibroblast-specific deletion of Glis3 in mice alleviated pathological features of chronic colitis. Taken together, our findings identify a critical immune-stromal cell circuit that functions as a central node in the inflammation-fibrosis cycle.