Coexistence of regulatory B cells and regulatory T cells in tumor-infiltrating lymphocyte aggregates is a prognostic factor in patients with breast cancer

Ishigami, Emi; Sakakibara, Masahiro; Sakakibara, Junta; Masuda, Takuya; Fujimoto, Hiroshi; Hayama, Shouko; Nagashima, Takeshi; Sangai, Takafumi; Nakagawa, Ayako; Nakatani, Yukio; Otsuka, Masayuki

doi:10.1007/s12282-018-0910-4

Cited by 77 publications

(61 citation statements)

References 40 publications

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“…29 In breast cancer patients, metastasis-free survival was significantly shorter for patients with the coexistence of Tregs and Bregs in TIL aggregates compared to Tregs alone, suggesting their interdependence in the development of breast cancer metastasis. 30…”

Section: Adaptive Immune Responsesmentioning

confidence: 99%

If we build it they will come: targeting the immune response to breast cancer

et al. 2019

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Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance.

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Section: Adaptive Immune Responsesmentioning

confidence: 99%

If we build it they will come: targeting the immune response to breast cancer

et al. 2019

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“…In human cancer, Breg were described by either phenotyping, direct detection of immunoinhibitory cytokines or surface molecules, and/or immunosuppressive function 4,[9][10][11][12][13] .Often Breg frequencies increase with tumor progression and are enriched in tumors compared to peripheral blood or adjacent normal tissue. Increased IL-10 + B cell numbers can also be accompanied by increased numbers of CD4 + CD25 +/high CD127 low/and Foxp3 + Tregs in tumor tissues 10,12,14,15 which were independently associated with tumor progression or reduced patient survival.In human melanoma, up to 33% of the immune cells can be TAB 16,17 and phenotypic analysis has revealed CD20+ TAB (reviewed in 18 ) and CD138 + or IgA + CD138 + plasma cells 17,19 .Conclusions about their impact on disease progression and outcome are inconsistent. So far, no data exist for TAB functions in murine models of melanoma highlighting the need for studies in melanoma patients and tumor samples.…”

mentioning

confidence: 99%

“…Often Breg frequencies increase with tumor progression and are enriched in tumors compared to peripheral blood or adjacent normal tissue. Increased IL-10 + B cell numbers can also be accompanied by increased numbers of CD4 + CD25 +/high CD127 low/and Foxp3 + Tregs in tumor tissues 10,12,14,15 which were independently associated with tumor progression or reduced patient survival.…”

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confidence: 99%

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

Griss

Bauer

Wagner

et al. 2018

Preprint

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Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Established mechanisms that underlie therapy response and resistance center on anti-tumor T cell responses.Here we show that tumor-associated B cells are vital to tumor associated inflammation.Autologous B cells were directly induced by melanoma conditioned medium, expressed proand anti-inflammatory factors, and differentiated towards a plasmablast-like phenotype in vitro .We could identify this phenotype as a distinct cluster of B cells in an independent public single-cell RNA-seq dataset from melanoma tumors. There, plasmablast-like tumor-associated B cells showed expression of CD8+T cell-recruiting chemokines such as CCL3, CCL4, CCL5 and CCL28. Depletion of tumor associated B cells in metastatic melanoma patients by anti-CD20 immunotherapy decreased overall inflammation and CD8+T cell numbers in the human melanoma TME. Conversely, the frequency of plasmablast-like B cells in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade in two independent cohorts. Tumor-associated B cells therefore orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.2 Cancers such as melanoma, lung, and kidney cancer often present with an inflamed but immunosuppressive tumor microenvironment (TME). Immune checkpoint blocking (ICB) antibodies have significantly improved cancer therapy by overcoming inhibition of T cell effector functions. Yet, a considerable number of patients does not benefit from ICB therapy 1 . It is therefore key to understand the mechanisms that regulate inflammation within the TME to develop novel therapies and improve patient survival. B cells promote both acute immune-associated inflammation for protection against foreign pathogens as well as chronic inflammation in autoimmune diseases and persistent infection. Mouse cancer models show that tumor-associated B cells (TAB) promote tumor inflammation 2,3 but may also inhibit anti-tumor T cell-dependent therapy responses 4-7 . The immuno-inhibitory function of TAB in these models resembles that of regulatory B cells (Breg), which are an established source of inhibitory cytokines such as IL-10 and TGF-b (reviewed in 8 ). In human cancer, Breg were described by either phenotyping, direct detection of immunoinhibitory cytokines or surface molecules, and/or immunosuppressive function 4,[9][10][11][12][13] .Often Breg frequencies increase with tumor progression and are enriched in tumors compared to peripheral blood or adjacent normal tissue. Increased IL-10 + B cell numbers can also be accompanied by increased numbers of CD4 + CD25 +/high CD127 low/and Foxp3 + Tregs in tumor tissues 10,12,14,15 which were independently associated with tumor progression or reduced patient survival.In human melanoma, up to 33% of the immune cells can be TAB 16,17 and phenotypic analysis has revealed CD20+ TAB (reviewed in 18 ) and CD1...

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“…Patients with prostate cancer bone metastasis have high levels of functional Tregs in the bone marrow, causing the immunosuppressive TME [12]. Regulatory B cells (Bregs) can promote immunosuppressive microenvironment even further by converting CD4+ T cells into Tregs [13,14] and inducing myeloid cells to become immunosuppressive by increasing expression of PD-L1 and production of immunosuppressive cytokines such as transforming growth factor β (TGFβ) and IL-10 [15]. Furthermore, tumor-associated regulatory B cells are needed for TGFβ-dependent pro-metastatic function of myeloid-derived suppressor cells (MDSCs) [16].…”

Section: Immune Cells and Metastasismentioning

confidence: 99%

Immunotherapies and Metastatic Cancers: Understanding Utility and Predictivity of Human Immune Cell Engrafted Mice in Preclinical Drug Development

Kähkönen¹,

Halleen²,

Bernoulli

2020

Cancers

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Metastases cause high mortality in several cancers and immunotherapies are expected to be effective in the prevention and treatment of metastatic disease. However, only a minority of patients benefit from immunotherapies. This creates a need for novel therapies that are efficacious regardless of the cancer types and metastatic environments they are growing in. Preclinical immuno-oncology models for studying metastases have long been limited to syngeneic or carcinogenesis-inducible models that have murine cancer and immune cells. However, the translational power of these models has been questioned. Interactions between tumor and immune cells are often species-specific and regulated by different cytokines in mice and humans. For increased translational power, mice engrafted with functional parts of human immune system have been developed. These humanized mice are utilized to advance understanding the role of immune cells in the metastatic process, but increasingly also to study the efficacy and safety of novel immunotherapies. From these aspects, this review will discuss the role of immune cells in the metastatic process and the utility of humanized mouse models in immuno-oncology research for metastatic cancers, covering several models from the perspective of efficacy and safety of immunotherapies.

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Coexistence of regulatory B cells and regulatory T cells in tumor-infiltrating lymphocyte aggregates is a prognostic factor in patients with breast cancer

Cited by 77 publications

References 40 publications

If we build it they will come: targeting the immune response to breast cancer

If we build it they will come: targeting the immune response to breast cancer

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

Immunotherapies and Metastatic Cancers: Understanding Utility and Predictivity of Human Immune Cell Engrafted Mice in Preclinical Drug Development

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