IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia

Pylayeva-Gupta, Yuliya; Das, Shipra; Handler, Jesse; Hajdu, Cristina; Coffre, Maryaline; Koralov, Sergei B.; Bar–Sagi, Dafna

doi:10.1158/2159-8290.cd-15-0843

Cited by 294 publications

(267 citation statements)

References 32 publications

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“…Interestingly, recent work in Kras-driven PDAC GEMMs has shown that depletion of tumor stroma or targeting Cxcl12 from tumor-associated fibroblasts exhibits a synergistic effect with immune checkpoint therapies (Feig et al 2013;Ozdemir et al 2014), suggesting that conditioning of the PDAC stroma might be a prerequisite for attaining therapeutic responses to immunotherapies. In addition, stroma-derived Cxcl13 has been shown to induce the infiltration of B-cell subpopulations and promote tumor growth, likely through programming TAMs toward an M2 phenotype (Gunderson et al 2015;Lee et al 2015;Pylayeva-Gupta et al 2015). Importantly, targeting Bruton's tyrosine kinase (BTK), a key kinase for B-cell and TAM function, suppresses tumor progression in an orthotopic PDAC mouse model through the induction of TILs (Gunderson et al 2015).…”

Section: Prospect Of Pdac Immunotherapymentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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Section: Prospect Of Pdac Immunotherapymentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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“…Several recent investigations in mouse cancer models have revealed the existence of protumorigenic regulatory B cells (Breg; refs. [16][17][18]. Here, we identifi ed a novel protumorigenic PD-1 hi B-cell subset in human hepatocellular carcinoma (HCC).…”

Section: Introductionmentioning

confidence: 99%

PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression

et al. 2016

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B cells often constitute abundant cellular components in human tumors. Regulatory B cells that are functionally defi ned by their ability to produce IL10 downregulate infl ammation and control T-cell immunity. Here, we identifi ed a protumorigenic subset of B cells that constitutively expressed higher levels of programmed cell death-1 (PD-1) and constituted ∼ 10% of all B cells in advanced-stage hepatocellular carcinoma (HCC).

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“…30 Genetic models of oncogenesis have been used extensively to document immune-mediated tumor promotion in solid cancers. 25,30,[40][41][42] However, evidence of immunosurveillance and immunoediting in genetic models of "solid," non-lymphoid, oncogenesis have been sparse and have yielded conflicting results. 34,43 For example, in the p53 ¡/C model of oncogenesis, knockout of Ifngr1 accelerated tumor onset and the spectrum of tumors of non-lymphoid origins.…”

Section: Discussionmentioning

confidence: 99%

Immunosurveillance and immunoediting in MMTV-PyMT-induced mammary oncogenesis

et al. 2017

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Evidence of cancer immunosurveillance and immunoediting processes has been primarily demonstrated in mouse models of chemically induced oncogenesis. Although these models are very tractable, they are characterized by high mutational loads that represent a minority of human cancers. In this study, we sought to determine whether cancer immunosurveillance and immunoediting could be demonstrated in a more clinically relevant oncogene-induced model of carcinogenesis, the MMTV-PyMT (PyMT) mammary carcinoma model. This model system in the FVB/NJ strain background was previously used to demonstrate that adaptive immunity had no role in limiting primary cancer formation and in fact promoted metastasis, thus calling into question whether cancer immunosurveillance operated in preventing the development of breast cancer. Our current study in the C57BL/6 strain backgrounds provides a different conclusion, as we report here the existence of an adaptive immunosurveillance of PyMT mammary carcinomas using two independent models of immune deficiency. PyMT mice bred onto a Rag1 ¡/¡ background or immune suppressed by chronic tacrolimus therapy both demonstrated accelerated development of mammary carcinomas. By generating a bank of cell lines from these animals, we further show that a subset of PyMT cell lines had delayed growth after transplantation into wild-type (WT) syngeneic, but not immune-deficient hosts. This reduced growth rate in immunocompetent animals was characterized by an increase in immune cell infiltration and tissue differentiation. Furthermore, loss of the immune cell infiltration that characterized immunoediting of slow growing cell lines, changed them into fast growing variants capable of progressing in the immunocompetent model. In conclusion, our study provides evidence that immunosurveillance and immunoediting of PyMT-derived cell lines modulate tumor progression in this oncogene-induced model of cancer.

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IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia

Cited by 294 publications

References 32 publications

Genetics and biology of pancreatic ductal adenocarcinoma

Genetics and biology of pancreatic ductal adenocarcinoma

PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression

Immunosurveillance and immunoediting in MMTV-PyMT-induced mammary oncogenesis

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