Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients

Fremd, Carlo; S, Stefanovic; Beckhove, Philipp; Pritsch, Maria; Lim, Hendry; Wallwiener, Markus; Heil, Joerg; Golatta, Michael; Rom, Joachim; Sohn, Christof; Schneeweiß, Andreas; Schuetz, Florian; Domschke, Christoph

doi:10.1080/2162402x.2015.1057387

Cited by 43 publications

(32 citation statements)

References 38 publications

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“…Tn and sTn expression by several types of tumors is associated with metastatic potential and poor prognosis (1). Patients who produce Ab against TACAs and mucins, either naturally or in response to vaccination, may have improved survival outcomes (4–9). However, eliciting protective antibody responses against these carbohydrate antigens has proven challenging.…”

Section: Introductionmentioning

confidence: 99%

PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

Haro

Littrell

Yin

et al. 2016

Cancer Immunology Research

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Tn is a carbohydrate antigen uniquely exposed on tumor mucins and thus, an ideal target for immunotherapy. However, it has been difficult to elicit protective antibody responses against Tn antigen and other tumor associated carbohydrate antigens. Our study demonstrates this can be attributed to PD-1 immuno-inhibition. Our data show a major role for PD-1 in suppressing mucin- and Tn-specific B-cell activation, expansion, and antibody production important for protection against Tn-bearing tumor cells. These Tn/mucin-specific B cells belong to the innate-like B-1b cell subset typically responsible for T cell–independent antibody responses. Interestingly, PD-1–mediated regulation is B cell–intrinsic and CD4+ cells play a key role in supporting Tn/mucin-specific B cell antibody production in the context of PD-1 deficiency. Mucin-reactive antibodies produced in the absence of PD-1 inhibition largely belong to the IgM subclass and elicit potent antitumor effects via a complement-dependent mechanism. The identification of this role for PD-1 in regulating B cell–dependent antitumor immunity to Tn antigen highlights an opportunity to develop new therapeutic strategies targeting tumor associated carbohydrate antigens.

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Section: Introductionmentioning

confidence: 99%

PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

Haro

Littrell

Yin

et al. 2016

Cancer Immunology Research

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“…Indeed, it has been reported that the increased IgG2 values tend to correlate with prolonged breast patient survival but not IgG1, IgG3 and IgG4 levels. 26 Although the significant roles of IgG2 in the antitumor response remain to be investigated, the present study suggests that the IgG2 subclass may be more effective for tumor therapy.…”

Section: Discussionmentioning

confidence: 71%

B lymphocytes repress hepatic tumorigenesis but not development in Hras12V transgenic mice

et al. 2017

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Increasing reports show noninflammation underlying HCC, challenging our understanding of the roles of the immune system in hepatocarcinogenesis. By exploring a mouse model of hepatic tumor induced by hepatocyte-specific expression of the Hras12V oncogene without obvious inflammation, we found that the proportion of B cells, but not T cells, progressively and significantly decreased in 3, 5-month-old transgenic mice (Tg) compared with non-transgenic mice. Notably, the proportions of total and activated B and T cells all significantly decreased in 9-month-old Tg with multiple massive hepatic tumors. Together with the decreased B cell proportion, serum IgG1/2 also significantly decreased in 5, 9-month-old Tg. Interestingly, homozygous Tg showed significantly higher B cell proportion and IgG2 levels, accompanied by significantly lower incidences of liver nodules but not adenomas and carcinomas compared with heterozygous Tg. Treatment of Tg with PCI-32765, a potent Bruton's tyrosine kinase (BTK) inhibitor for suppressing B cell proliferation and activation, significantly decreased the B cell proportion and IgG2 levels, accompanied by a significantly higher incidence of liver nodules, but had no effects on adenoma and carcinoma. Treatment of Tg with insulin-like growth factor 1 (IGF-1) significantly increased the B cell proportion and IgG2 levels, accompanied by a significantly lower incidence of liver nodules and carcinoma, but had no effects on adenoma. Conclusively, B cells and IgG2 may play important roles in suppressing hepatic tumorigenesis, but not development. In addition, hepatocyte-specific expression of the ras oncogene may play roles in suppressing B cells, while developed hepatic tumors suppress both B and T cells.

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“…BC has been recognized to be immunogenic, which has involved multiple putative tumor-associated antigens (TAAs), such as HER-2 and Mucin 1 (MUC1) [30,31]. Note worthily, these TAAs have been treated as the targets for developing new cancer vaccine and bispeci c antibody (bsAbs) over the past decade, among which, some have been translated into tumor-speci c immune responses and have been veri ed to be clinically bene cial [32].…”

Section: Discussionmentioning

confidence: 99%

Immune-related Gene Data-based Molecular Subtyping Related to the Prognosis for Breast Cancer Patients

et al. 2020

Preprint

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Background Breast cancer (BC), the most frequently seen malignant tumor in female, is associated with increasing morbidity and mortality year by year. Generally, the available treatments for BC include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. Typically, as molecular biology, immunology and pharmacogenomics develop, a growing amount of evidence has suggested that immunocyte infiltration into tumor microenvironment, together with the immunophenotype of tumor cells, would remarkably influence the development and malignant transformation of tumor; as a result, immunotherapy has become a promising therapy for treating BC, which would also affect patient prognosis.Methods In this study, samples collected from TCGA and ImmPort database would be analyzed to search for specific immune-related genes affecting BC patient prognosis. A total of 64 immune-related genes with significant correlation with patient prognosis had been screened and performed shrinkage estimate, among which, 29 most representative ones with significant correlation with patient prognosis had been selected and utilized to establish the prognosis prediction model for BC patients (as referred to as the RiskScore equation). Thereafter, samples in both training set and test set would be substituted into the model, respectively; meanwhile, BC patients would also be divided based on the median RiskScore to assess the efficiency, accuracy and stability of the model in predicting and classifying patient prognosis. Subsequently, functional annotations, GO and KEGG signaling pathway enrichment analysis would be carried out among the 29 as-screened immune-related genes.Results The results found that, these 29 genes could be mainly enriched to numerous BC- and immune microenvironment-related pathways. Eventually, the relationship between RiskScore and the sample clinical features as well as the signaling pathways would be analyzed.Conclusions Our findings indicate that, the prognosis prediction model RiskScore established on the basis of the expression profiles of 29 immune-related genes has displayed high prediction accuracy and stability in identifying the immune features, which can guide the clinicians to diagnose and predict the prognosis for different immunophenotypes, in the meantime of offering numerous therapeutic targets for precisely treating BC in clinic using the identified subtype-specific immune molecules.

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Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients

Cited by 43 publications

References 38 publications

PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

B lymphocytes repress hepatic tumorigenesis but not development in Hras12V transgenic mice

Immune-related Gene Data-based Molecular Subtyping Related to the Prognosis for Breast Cancer Patients

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