Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

Bianchi, Anna; Silva, Iago De Castro; Deshpande, Nilesh; Singh, Samara; Mehra, Siddharth; Garrido, Vanessa T.; Guo, Xinyu; Nivelo, Luis A.; Kolonias, Despina; Saigh, Shannon J.; Wieder, Eric; Rafie, Christine I.; Dosch, Austin R.; Zhou, Zhiqun; Umland, Oliver; Amirian, Haleh; Ogobuiro, Ifeanyichukwu; Zhang, Jian; Ban, Yuguang; Shiau, Carina; Nagathihalli, Nagaraj S.; Montgomery, Elizabeth A.; Hwang, William L.; Brambilla, Roberta; Komanduri, Krishna V.; Villarino, Alejandro V.; Toska, Eneda; Stanger, Ben Z.; Gabrilovich, Dmitry I.; Merchant, Nipun B.; Datta, Jashodeep

doi:10.1158/2159-8290.cd-22-1046

Cited by 36 publications

(32 citation statements)

References 60 publications

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“…Of note, CXCR2 was found highly expressed in NET_IL1B+ and NET_PDE4B+ neutrophils, which was reported as a tumor CXCL1 target gene and also can induce T cell terminated (Supplementary Fig. 3c ) 45 . At the same time, a recent study also observed the expression of CXCL2 can induce the migration of neutrophils from the peripheral circuit to TME and might account for the liver metastasis after gemcitabine treatment, which might form feedforward recruitment of anti-tumor neutrophils and melatonin was validated to induced the expression of tumor cells rather than macrophages to recruit the neutrophils by upregulated CXCL2 42 , 46 .…”

Section: Discussionmentioning

confidence: 92%

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Fu,

Tao,

et al. 2024

npj Precis. Onc.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm characterized by a poor prognosis and limited therapeutic strategy. The PDAC tumor microenvironment presents a complex heterogeneity, where neutrophils emerge as the predominant constituents of the innate immune cell population. Leveraging the power of single-cell RNA-seq, spatial RNA-seq, and multi-omics approaches, we included both published datasets and our in-house patient cohorts, elucidating the inherent heterogeneity in the formation of neutrophil extracellular traps (NETs) and revealed the correlation between NETs and immune suppression. Meanwhile, we constructed a multi-omics prognostic model that suggested the patients exhibiting downregulated expression of NETs may have an unfavorable outcome. We also confirmed TLR2 as a potent prognosis factor and patients with low TLR2 expression had more effective T cells and an overall survival extension for 6 months. Targeting TLR2 might be a promising strategy to reverse immunosuppression and control tumor progression for an improved prognosis.

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Section: Discussionmentioning

confidence: 92%

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Fu,

Tao,

et al. 2024

npj Precis. Onc.

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“…PMN-MDSCs directly inhibit T cell proliferation, express PDL-1 and immunosuppressive cytokines and mobilizes Treg [37]. Indeed, PMN-MDSCs are the dominant source of TNFα leading to stromal inflammation and immune tolerance to promote therapeutic resistance in PDAC [38]. This was observed by using the etanercept, a soluble form of TNFR2, to block TNFα.…”

Section: Resultsmentioning

confidence: 99%

TNFR2 blockade promotes anti-tumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion

Debesset,

Pilon,

Meunier

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing TNFα receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in PDAC patients. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing anti-tumoral responses.. PDAC patients exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells. By flow cytometry and single cell RNAseq analysis, we identified two Treg populations in orthotopic mouse models: resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+ T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8+ T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAbs promoted stronger T cell activation, immunological memory, tumor growth inhibition, and improved survival in PDAC-bearing mice. Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for PDAC patients.

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“…Previously, our research has determined that CREB promotes transcriptional upregulation and secretion of pro-inflammatory chemokines/cytokines 38 . CREB mediated control in the secretion of immune modulatory factors helps facilitate the communication between epithelial and myeloid cells in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

CREB activation drives acinar to ductal reprogramming and promote pancreatic cancer progression in animal models of alcoholic chronic pancreatitis

Srinivasan,

Mehra,

Bianchi

et al. 2024

Preprint

Self Cite

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BACKGROUND AND AIMSIn vivoinduction of alcoholic chronic pancreatitis (ACP) causes significant acinar damage, increased fibroinflammatory response, and heightened activation of cyclic response element binding protein 1 (CREB) when compared with alcohol (A) or chronic pancreatitis (CP) mediated pancreatic damage. However, the study elucidating the cooperative interaction between CREB and the oncogenicKrasG12D/+(Kras*) in promoting pancreatic cancer progression with ACP remains unexplored.METHODSExperimental ACP induction was established in multiple mouse models, followed by euthanization of the animals at various time intervals during the recovery periods. Tumor latency was determined in these mice cohorts. Here, we established CREB deletion (Crebfl/fl) inPtf1aCreERTM/+;LSL-KrasG12D+/−(KC) genetic mouse models (KCC−/−). Western blot, phosphokinase array, and qPCR were used to analyze the pancreata ofPtf1aCreERTM+/−,KCandKCC−/−mice. The pancreata of ACP-inducedKCmice were subjected to single-cell RNA sequencing (scRNAseq). Further studies involved conducting lineage tracing and acinar cell explant cultures.RESULTSACP induction inKCmice had detrimental effects on the pancreatic damage repair mechanism. The persistent existence of acinar cell-derived ductal lesions demonstrated a prolonged state of hyperactivated CREB. Persistent CREB activation leads to acinar cell reprogramming and increased pro-fibrotic inflammation inKCmice. Acinar-specificCrebablation reduced advanced PanINs lesions, hindered tumor progression, and restored acinar cell function in ACP-induced mouse models.CONCLUSIONSOur findings demonstrate that CREB cooperates withKras*to perpetuate an irreversible ADM and PanIN formation. Moreover, CREB sustains oncogenic activity to promote the progression of premalignant lesions toward cancer in the presence of ACP.

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Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

Cited by 36 publications

References 60 publications

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

TNFR2 blockade promotes anti-tumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion

CREB activation drives acinar to ductal reprogramming and promote pancreatic cancer progression in animal models of alcoholic chronic pancreatitis

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