Recruiting lymphocytes
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STAT6 mutations compensate for CREBBP mutations and hyperactivate IL4/STAT6/RRAGD/mTOR signaling in follicular lymphoma
Activating mutations in STAT6 are common in Follicular Lymphoma (FL) and transformed FL and various other B cell lymphomas. Here, we report RNA-seq based gene expression data on normal human lymph node derived B lymphocytes (NBC; N = 6), and primary human FL WT (N = 11) or mutant (N = 4) for STAT6 before and after ex vivo stimulation with IL4. We found that STAT6 mutants result in broad based augmentation of IL4-induced gene expression. Unexpectedly, in FL with WT STAT6 we measured reduced baseline and IL4-induced gene expression levels when compared with NBC lymphocytes or FL with STAT6 mutations. We tracked the attenuated IL4/JAK/STAT6 response to co-existing CREBBP mutations and experimentally verified that intact CREBBP is required for the induction of many IL4-induced genes. One of the IL4-induced genes here identified is RRAGD, a small G-protein involved in lysosomal mTOR activation. We show that IL4 treatment induced RRAGD expression, that RRAGD is required for mTOR activation in lymphoma cells and that IL4-enhanced BCR signaling induced mTOR activation. The IL4 and BCR-induced mTOR activation was reduced by CREBBP mutants and augmented by mutant STAT6, establishing a link between STAT6 mutations and mTOR regulated pro-growth pathways in lymphoma.
Neuromedin U promotes human type 2 immune responses
Type 2 immunity mediates the immune responses against parasites and allergic stimuli. Evidence from studies of cell lines and animals implies that neuromedin U (NmU) acts as a pro-inflammatory mediator of type 2 inflammation. However, the role of NmU in human type 2 immunity remains unclear. Here we investigated the expression of NmU in human blood and airways, and the expression of NmU receptors by human immune cells in blood and lung tissue. We detected human NmU (hNmU-25) in blood and airways with higher concentrations in the latter. NmU receptor 1 (NmUR1) was expressed by most human immune cells with higher levels in type 2 cells including type 2 T helpers, type 2 cytotoxic T cells, group-2 innate lymphoid cells and eosinophils, and was upregulated in lung-resident and activated type 2 cells. We also assessed the effects of NmU in these cells. hNmU-25 elicited type 2 cytokine production by type 2 lymphocytes and induced cell migration, including eosinophils. hNmU-25 also enhanced the type 2 immune response to other stimuli, particularly prostaglandin D2. These results indicate that NmU could contribute to the pathogenic processes of type 2 immunity-mediated diseases in humans via its pro-inflammatory effects on type 2 lymphocytes and eosinophils.
Tri-specific tribodies targeting 5T4, CD3, and immune checkpoint drive stronger functional T-cell responses than combinations of antibody therapeutics
One of the most promising cancer immunotherapies is based on bi-specific T-cell engagers (BiTEs) that simultaneously bind with one arm to a tumor-associated antigen on tumor cells and with the other one to CD3 complex on T cells to form a TCR-MHC independent immune synapse. We previously generated four novel tri-specific tribodies made up of a Fab targeting 5T4, an oncofetal tumor antigen expressed on several types of tumors, a scFv targeting CD3 on T cells, and an additional scFv specific for an immune checkpoint (IC), such as PD-1, PD-L1 or LAG-3. To verify their advantages over the combinations of BiTEs (CD3/TAA) with IC inhibitors, recently used to overcome tumor immunosuppressive environment, here we tested their functional properties in comparison with clinically validated mAbs targeting the same ICs, used alone or in combination with a control bi-specific devoid of immunomodulatory scFvs, called 53 P. We found that the novel tri-specific tribodies activated human peripheral blood mononuclear cells more efficiently than clinically validated mAbs (atezolizumab, pembrolizumab, and relatlimab) either used alone or in combination with 53 P, leading to a stronger tumor cytotoxicity and cytokines release. In particular, 53L10 tribody targeting PD-L1 displayed much more potent effects than the combination of 53 P with all the clinically validated mAbs and led to complete tumor regression in vivo, showing much higher efficacy than the combination of 53 P and atezolizumab. We shed light on the molecular basis of this potentiated anti-tumor activity by evidencing that the insertion of the anti-PD-L1 moiety in 53L10 led not only to stronger binding of the tri-specific to tumor cells but also efficiently blocked the effects of increased PD-L1 on tumor cells, induced by IFNγ secretion also due to T-cell activation. These results are important also for the design of novel T-cell engagers targeting other tumor antigens.
Characterization of the landscape of the intratumoral microbiota reveals that Streptococcus anginosus increases the risk of gastric cancer initiation and progression
As a critical component of the tumour immune microenvironment (TIME), the resident microbiota promotes tumorigenesis across a variety of cancer types. Here, we integrated multiple types of omics data, including microbiome, transcriptome, and metabolome data, to investigate the functional role of intratumoral bacteria in gastric cancer (GC). The microbiome was used to categorize GC samples into six subtypes, and patients with a high abundance of Streptococcus or Pseudomonas had a markedly worse prognosis. Further assays revealed that Streptococcus anginosus (SA) promoted tumour cell proliferation and metastasis while suppressing the differentiation and infiltration of CD8+ T cells. However, antibiotic treatment significantly suppressed tumorigenesis in SA+ mice in vivo. We further demonstrated that the SA arginine pathway increased the abundance of ornithine, which may be a major contributor to reshaping of the TIME. Our findings demonstrated that SA, a novel risk factor, plays significant roles in the initiation and progression of GC, suggesting that SA might be a promising target for the diagnosis and treatment of GC.
Temporal profiling of human lymphoid tissues reveals coordinated defense against viral challenge
Adaptive immunity is generated in lymphoid organs, but how these structures defend themselves during infection in humans is unknown. The nasal epithelium is a major site of viral entry, with adenoid nasal-associated lymphoid tissue (NALT) generating early adaptive responses. In the present study, using a nasopharyngeal biopsy technique, we investigated longitudinal immune responses in NALT after a viral challenge, using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as a natural experimental model. In acute infection, infiltrating monocytes formed a subepithelial and perifollicular shield, recruiting neutrophil extracellular trap-forming neutrophils, whereas tissue macrophages expressed pro-repair molecules during convalescence to promote the restoration of tissue integrity. Germinal center B cells expressed antiviral transcripts that inversely correlated with fate-defining transcription factors. Among T cells, tissue-resident memory CD8 T cells alone showed clonal expansion and maintained cytotoxic transcriptional programs into convalescence. Together, our study provides unique insights into how human nasal adaptive immune responses are generated and sustained in the face of viral challenge.
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