Type I interferon is selectively required by dendritic cells for immune rejection of tumors

Diamond, Mark S.; Kinder, Michelle; Matsushita, Hirokazu; Mashayekhi, Mona; Dunn, Gavin P.; Archambault, Jessica M.; Lee, Hsiaoju; Arthur, Cora D.; White, J. Michael; Kalinke, Ulrich; Murphy, Kenneth M.; Schreiber, Robert D.

doi:10.1084/jem.20101158

Cited by 885 publications

(804 citation statements)

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“…Therefore, a defect in the innate immune cell compartment upstream of CD8 + T cells in IFNAR −/− and STAT1 −/− mice is the likely culprit. Interestingly, mice with a deletion of IFNAR in CD11c + DCs were unable to reject a model of immunogenic sarcoma [32]. Furthermore, IFNAR −/− or STAT1 −/− mice exhibit a defect in the recruitment of CD8α + DCs to the tumors [31] and IFNAR −/− CD8α + DCs showed impairment in cross-presentation of tumor-derived antigens to CD8 + T cells in vivo [32].…”

Section: The Central Role For Type I Ifns and Batf3 Dcsmentioning

confidence: 99%

“…The pivotal role of Batf3 DCs in anti-tumor immunity is evident in Batf3 −/− mice, which fail to reject immunogenic tumors. Using mixed bone marrow chimeras and conditional knockout models, two independent experimental approaches conclusively demonstrated that type I IFN signaling in Batf3 DCs is required for the immune control of tumor growth [31,32]. Notably, during infection of Batf3 −/− mice with intracellular bacteria, Batf1 and Batf2 can interact with IRF8 and provide a compensatory restoration of the abundance and functions of Batf3 DCs via a signaling mechanism dependent on IL-12 and IFN-γ, but independent of T cells or B cells [40].…”

Section: The Central Role For Type I Ifns and Batf3 Dcsmentioning

confidence: 99%

“…The role of type I IFNs is critical in the early stages of anti-tumor immune response, because a blocking antibody against this cytokine prevented rejection of a transplantable immunogenic tumor if administered within the first 4-6 days of tumor growth, but had no effect at later time points [32]. Indeed, at this early stage, type I IFN is produced by CD11c + cells in the tumor-draining lymph node in the B16 melanoma model [31].…”

Section: The Central Role For Type I Ifns and Batf3 Dcsmentioning

confidence: 99%

“…However, in the tumor setting the nature of such tumor-related factors and the main pathways activated during carcinogenesis have only recently begun to be elucidated. The association between a type I IFN gene signature and T cell infiltration in human cancers as well as mouse tumor models allowed a focus on innate signaling pathways capable of inducing type I IFNs [23,31,32]. As described above, deficiency in IFNAR or the downstream transcription factor STAT1 in host cells resulted in impaired priming of T cells against tumor-associated antigens [31,32].…”

Section: The Sting Pathway and Innate Immune Sensing Of Tumorsmentioning

confidence: 99%

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Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

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A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.

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Section: The Central Role For Type I Ifns and Batf3 Dcsmentioning

confidence: 99%

Section: The Central Role For Type I Ifns and Batf3 Dcsmentioning

confidence: 99%

Section: The Central Role For Type I Ifns and Batf3 Dcsmentioning

confidence: 99%

Section: The Sting Pathway and Innate Immune Sensing Of Tumorsmentioning

confidence: 99%

See 2 more Smart Citations

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

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“…Besides its recently demonstrated effects on angiogenic processes, 4 activation of tumor specific CD8 1 T cells, 49 and its contribution to DCmediated cross-presentation of tumor antigens, 50 it apparently plays an important role in the regulation of the life span and apoptosis of tumor-promoting neutrophilic granulocytes. This again highlights the tremendous therapeutic potential of IFN-b.…”

Section: Tumor Immunologymentioning

confidence: 99%

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Andzinski

Lienenklaus

et al. 2014

Intl Journal of Cancer

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The importance of neutrophils in tumor immune surveillance, invasive growth and angiogenesis becomes increasingly clear. Many of neutrophil activities are controlled by endogenous IFN-b. Here, we provide evidence that endogenous IFN-b is regulating the apoptosis of pro-angiogenic tumor infiltrating neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Accordingly, the life span of tumor associated neutrophils (TANs) is remarkably prolonged in tumor bearing Ifnb1 2/2 mice compared to wild type controls. Lower expression of Fas, reactive oxygen species, active Caspase 3 and 9, as well as a change in expression pattern of proapoptotic and antiapoptotic members of the Bcl-2 family and the major apoptosome constituent Apaf-1 is observed under such conditions. In line with inhibition of apoptosis and the prolonged neutrophil survival, in the absence of endogenous IFN-b, a strong enhancement of G-CSF expression and PI3 Kinase phosphorylation is detected. These data explain the increased longevity of tumor infiltrating neutrophils and the accumulation of such cells in tumors. Taken together, our findings add to the important role of Type I IFN in immune surveillance against cancer.Neutrophilic granulocytes are the most abundant white blood cells in circulation, that are released from the bone marrow as terminally differentiated, nondividing cells. 1 Besides their role in immunity, neutrophils strongly influence growth, metastasis, 2 angiogenesis 3,4 and immune surveillance 5 of tumors. In contrast to cells of the adaptive immune system, neutrophils need no activation to acquire an effector phenotype. In accordance with their pleiotropic function, neutrophils are equipped with a large array of effector molecules like proteolytic enzymes, antimicrobial proteins/peptides and are able to produce reactive oxygen species. 6 Due to their potential toxicity against host tissue, the life span of such cells is strictly regulated. 7 In the absence of noxious or inflammatory stimuli, neutrophils are removed from circulation by apoptosis shortly after their emigration from the bone marrow. However, several proinflammatory cytokines have been shown to influence the longevity of neutrophils. 8 Type I interferons (IFNs) were first identified as factors responsible for the phenomenon of viral interference. In the meantime, they are recognized to influence a broad variety of biological processes, such as maintenance of cellular homeostasis, 9 hematopoiesis, 10 lymphocyte development 11 and apoptosis of dendritic 12 or CD4 1 T cells 13 besides their role in infections. In addition, Type I IFNs display strong antitumor effects by exhibiting direct antiproliferative and proapoptotic effects on tumor cells 14 as well as supporting systemic immunity against tumor targets by up-regulation of MHC class I expression, enhancement of cytotoxic T cell responses and activation of natural killer cells and macrophages. 15 Nevertheless, the mechanism of how Type I IFNs contribute to immune surveillance against tumo...

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Role of Local Radiation Therapy in Cancer Immunotherapy

2015

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The recent success of cancer immunotherapy has demonstrated the power of the immune system to clear tumors, generating renewed enthusiasm for identifying ways to induce antitumor immune responses in patients. Natural antitumor immune responses are detectable in a fraction of patients across multiple malignant neoplasms and can be reactivated by targeting rate-limiting immunosuppressive mechanisms. In most patients, however, interventions to induce a de novo antitumor immune response are necessary. We review growing evidence that radiation therapy targeted to the tumor can convert it into an in situ tumor vaccine by inducing release of antigens during cancer cell death in association with proinflammatory signals that trigger the innate immune system to activate tumor-specific T cells. In addition, radiation's effects on the tumor microenvironment enhance infiltration of activated T cells and can overcome some of the barriers to tumor rejection. Thus, the complementary effects of radiation on priming and effector phases of antitumor immunity make it an appealing strategy to generate immunity against a patient's own individual tumor, that through immunological memory, can result in long-lasting systemic responses. Several anecdotal cases have demonstrated the efficacy of combining radiation with available immunotherapies, and results of prospective trials are forthcoming.

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Type I interferon is selectively required by dendritic cells for immune rejection of tumors

Abstract: Dendritic cell responsiveness to type I interferon is required for the generation of antitumor T cell responses and tumor rejection.

Cited by 885 publications

References 66 publications

Innate immune signaling and regulation in cancer immunotherapy

Innate immune signaling and regulation in cancer immunotherapy

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Role of Local Radiation Therapy in Cancer Immunotherapy

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