Bruton Tyrosine Kinase–Dependent Immune Cell Cross-talk Drives Pancreas Cancer

Gunderson, Andrew; Kaneda, Megan M.; Tsujikawa, Takahiro; Nguyen, Abraham V.; Affara, Nesrine I.; Ruffell, Brian; Gorjestani, Sara; Liudahl, Shannon M.; Truitt, Morgan; Olson, Peter; Kim, Grace; Hanahan, Douglas; Tempero, Margaret A.; Sheppard, Brett C.; Irving, Bryan; Chang, Betty; Varner, Judith A.; Coussens, Lisa M.

doi:10.1158/2159-8290.cd-15-0827

Cited by 426 publications

(394 citation statements)

References 49 publications

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“…Previous work from our group and others demonstrated in vivo Th1 skewing (21,22) with ibrutinib treatment in murine models. Here, we observed no significant changes in the percentage of T cells expressing intracellular Th1 (IFN-γ) or Th2 (IL-4) cytokines in CLL patients treated with ibrutinib.…”

Section: Ibrutinib Downregulates Immunosuppressive Molecules Cd200mentioning

confidence: 73%

“…In a CLL mouse model of bacterial infection, ibrutinib treatment led to a more than 2-fold increase in expansion of Th1 pathogen-specific T cells and corresponding suppression of Th2 immunity (21). Ibrutinib treatment also leads to a shift in macrophages toward a Th1-supportive phenotype and increases CD8 + T cell tumor infiltration in a mouse model of pancreatic cancer (22).…”

Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 99%

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Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

313

343

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BACKGROUND.Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS.Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8 + T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4 + T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025.

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Section: Ibrutinib Downregulates Immunosuppressive Molecules Cd200mentioning

confidence: 73%

Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 99%

Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

313

343

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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%

“…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). These preclinical data strongly support the ongoing clinical trials combining inhibitors of BTK and checkpoint blockade.…”

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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“…L'immunothérapie est un bon candidat, mais aucune approche de ce type n'est encore disponible pour traiter les cancers du pancréas, ce qui incite à mieux comprendre le rôle du système immunitaire dans ces tumeurs. Or, récemment, trois études ont mis en évidence des infiltrats de lymphocytes B dans l'adénocarcinome canalaire pancréatique par marquage immunohistologique de tumeurs et analyse de banques de données de transcriptome de tumeurs [4][5][6]. Dans chacune de ces études, les chercheurs identifient un mécanisme par lequel ces lymphocytes B pourraient exercer une action facilitant le dévelop-pement tumoral.…”

Section: Liens D'intérêtunclassified

Rôle protumoral des lymphocytes B dans le cancer du pancréas

Seiller

Dubois

2017

Med Sci (Paris)

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Bruton Tyrosine Kinase–Dependent Immune Cell Cross-talk Drives Pancreas Cancer

Cited by 426 publications

References 49 publications

Ibrutinib treatment improves T cell number and function in CLL patients

Ibrutinib treatment improves T cell number and function in CLL patients

Genetics and biology of pancreatic ductal adenocarcinoma

Rôle protumoral des lymphocytes B dans le cancer du pancréas

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