Anti–ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti–PD-1 or anti-CD137 mAb therapy

Stagg, John; Loi, Sherene; Divisekera, Upulie; Ngiow, Shin Foong; Duret, Helene; Yagita, Hideo; Teng, Michele W.L.; Smyth, Mark J.

doi:10.1073/pnas.1016569108

Cited by 427 publications

(361 citation statements)

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“…Further studies are necessary to identify the site of suppression in our model. PD-1-blocking antibodies are being discussed for clinical application in cancer (43), persistent viral hepatitis (44), and AIDS (45) as a means to invigorate suppressed or exhausted T-cell responses. Also antibody responses were found to be increased after PD-1 blockade, which our results suggest to be due to inhibition of T reg function.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Gotot¹,

Gottschalk²,

Leopold³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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123

108

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The mechanisms by which regulatory T cells (T regs ) suppress autoantibody production are unclear. Here we have addressed this question using transgenic mice expressing model antigens in the kidney. We report that T regs were essential and sufficient to suppress autoreactive B cells in an antigen-specific manner and to prevent them from producing autoantibodies. Most of this suppression was mediated through the inhibitory cell-surface-molecule programmed death-1 (PD-1). Suppression required PD-1 expression on autoreactive B cells and expression of the two PD-1 ligands on T regs . PD-1 ligation inhibited activation of autoreactive B cells, suppressed their proliferation, and induced their apoptosis. Intermediate PD-1 + cells, such as T helper cells, were dispensable for suppression. These findings demonstrate in vivo that T regs use PD-1 ligands to directly suppress autoreactive B cells, and they identify a previously undescribed peripheral B-cell tolerance mechanism against tissue autoantigens. Regulatory T cells (T regs ) are powerful suppressors of autoreactive T cells with high therapeutic potential (1-3). T regs also suppress auto-Ab production (4, 5). We recently showed in vivo that they do so in an antigen-specific (Ag-specific) manner (6, 7). These studies used rat insulin promoter HEL/OVA (ROH) mice expressing ovalbumin (OVA) and hen egg lysozyme (HEL) in pancreatic islet β-cells. Autoreactive OVA-and HEL-specific B cells, but not B cells specific for a foreign antigen, failed to proliferate in response to in vivo autoantigen (auto-Ag) challenge and instead underwent apoptosis in a strictly T reg -dependent fashion. T regs can affect B cells indirectly by suppressing the T-helper (Th) cells required for antibody production (8, 9). This did not rule out that T regs might also suppress B cells directly. Cell culture systems have revealed that CD25 + T regs can kill cocultured B cells (10-12). A recent in vivo study showed that T regs enter germinal centers and suppress B cells in this site (13,14). The question whether this occurred directly or indirectly remained open (15). This question is difficult to address in vivo because it requires an experimental system where T regs can suppress B cells but not Th cells.Another open question concerns the molecular mechanisms by which T regs suppress. In principle, T regs may suppress other T cells by (i) secreting inhibitory mediators; (ii) deprivation of survival factors; (iii) killing target cells by granzyme/perforin; and (iv) modulation of DCs by ligating inhibitory T-cell receptors (16,17). The exact contribution of these mechanisms in relevant in vivo situations and the mechanisms by which T regs suppress are unclear.Programmed death-1 (PD-1, CD279) is an activation-induced member of the extended CD28/CTLA-4 family that suppresses T cells (18-21). It has been associated with exhausted memory T cells in chronic viral infection (22,23) and with cytotoxic T-cell cross-tolerance (24). PD-1 has two known ligands, PDL-1 (B7-H1, CD274) and PDL-2 (B7-DC, CD273) (25,...

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Section: Discussionmentioning

confidence: 99%

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Gotot¹,

Gottschalk²,

Leopold³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

123

108

View full text Add to dashboard Cite

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“…Anti-PD-1 antibody therapy has been shown to enhance the response to radiotherapy and DC vaccines in established breast cancers (Verbrugge et al, 2012;Ge et al, 2013). Anti-PD-1 antibody also significantly improves the effectiveness of the anti-HER2 monoclonal antibody in immunocompetent mice (Stagg et al, 2011). Together, these studies suggest that anti-PD-1 may be used in combination with other therapies to improve the overall treatment efficacy in breast cancer.…”

Section: Immune Checkpoint Blockadementioning

confidence: 75%

Harnessing the immune system for the treatment of breast cancer

Jiang

2014

J. Zhejiang Univ. Sci. B

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Abstract:Standard treatment options for breast cancer include surgery, chemotherapy, radiation, and targeted therapies, such as adjuvant hormonal therapy and monoclonal antibodies. Recently, the recognition that chronic inflammation in the tumor microenvironment promotes tumor growth and survival during different stages of breast cancer development has led to the development of novel immunotherapies. Several immunotherapeutic strategies have been studied both preclinically and clinically and already have been shown to enhance the efficacy of conventional treatment modalities. Therefore, therapies targeting the immune system may represent a promising next-generation approach for the treatment of breast cancers. This review will discuss recent findings that elucidate the roles of suppressive immune cells and proinflammatory cytokines and chemokines in the tumor-promoting microenvironment, and the most current immunotherapeutic strategies in breast cancer.

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“…23 Recently, it was reported that the therapeutic effect of anti-HER2/neu did not require CD4 1 T cells, but did depend on both type I and type II interferon. 24 In other models of oncogenic blockade, however, it was reported that tumor regression did require CD4 1 T cells. 25 Thus, the detailed mechanism of CD4 1 T-cell activation and the role of these cells in antibody-mediated tumor regression are unclear.…”

Section: Antibody Therapymentioning

confidence: 99%

Targeting and utilizing primary tumors as live vaccines: changing strategies

Yang

Mortenson

2011

Cell Mol Immunol

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Tumor metastases and relapse are the major causes of morbidity and mortality in cancer. Although surgery, chemotherapy and/or radiation therapy can typically control primary tumor growth, metastatic and relapsing tumors are often inaccessible or resistant to these treatments. An adaptive immune response can be generated during these conventional treatments of the primary tumor, and presumably both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system. Thus, when established, this response should be able to control metastatic growth and tumor relapse. This review summarizes the mechanisms by which antitumor immune responses are generated, and recent findings supporting the hypothesis that many therapies targeting primary tumors can generate antitumor adaptive immune responses to prevent metastases and tumor relapse. Keywords: chemotherapy; immunotherapy; metastasis; radiotherapy; tumor vaccine INTRODUCTION Conventional treatments such as surgery and chemotherapy are effective means of eliminating or reducing primary tumor growth, but have not proved effective in eradicating metastases. Because metastatic disease may not respond similarly to chemotherapies used in treating the primary tumor, 1 recent research has focused on the importance of generating an antitumor immune response to control metastatic disease. Presumably, both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system; yet, there has been no clear strategy formulated in which a patient's own tumor tissues is used to generate an antitumor adaptive immune response for the eradication of metastases and prevention of relapse. Once tumors metastasize, curing the disease is difficult and rare. This review summarizes recent findings supporting the hypothesis that targeting primary tumors with both conventional and new therapies can potentially generate antitumor adaptive immune responses that prevent metastases and relapse.Due to the vast number of genetic changes associated with carcinogenesis, tumors express many neo-antigens and mutated antigens. Indeed, much evidence exists to indicate that many cancers are antigenic and thus recognizable by the adaptive immune system. 2 Mere recognition by adaptive immunity, however, is insufficient, given that these antigenic cancers rarely regress spontaneously. Effective antitumor immunity depends on both the presence of tumor-reactive lymphocyte precursors and means by which these precursor lymphocytes can be activated. Most T cells with high affinity to tissue-specific antigens are deleted in the thymus or later tolerized in the peripheral

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Anti–ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti–PD-1 or anti-CD137 mAb therapy

Cited by 427 publications

References 32 publications

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Harnessing the immune system for the treatment of breast cancer

Targeting and utilizing primary tumors as live vaccines: changing strategies

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