IL-15 Deficient Tax Mice Reveal a Role for IL-1α in Tumor Immunity

Rauch, Daniel A.; Harding, John C. S.; Ratner, Lee

doi:10.1371/journal.pone.0085028

Cited by 10 publications

(9 citation statements)

References 48 publications

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“…38 Therefore, these findings highlight the duality of IL-15 function with respect to the CD8 C T cell compartment and the influence on IL-6 levels. Furthermore, the contribution of IL-15 toward the final disease outcome is dependent on the inflammatory context, with deletion of the cytokine in a Toxoplamsa gondii infection model resulting in reduced disease severity and mortality, with lower levels of IL-6, TNFa and IL-1b produced compared to WT mice.…”

Section: Discussionmentioning

confidence: 74%

IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

et al. 2015

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IL-15 regulates the development, survival, and proliferation of multiple innate and adaptive immune cells and plays a dual role, inducing both tumor cell growth and antitumor immunity. However, the role of IL-15 in inflammation-induced cancer remains unclear. To explore this, we have compared the colon carcinoma burden of Il15 ¡/¡ and Il15ra ¡/¡ mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, Il15¡/¡ but not Il15ra ¡/¡ mice showed reduced survival, along with higher tumor incidence, colon weight, and tumor size. This suggests that low affinity IL-15 signaling via the shared IL-2Rb/gc decreases the risk for developing colitis-associated cancer. CD11c-Il15 mice, in which IL-15 expression is reconstituted in Il15 ¡/¡ mice under the control of the CD11c-promoter, showed that selective reconstitution of IL-15 in antigen-presenting cells restored the CD8 C T and NK cell compartments, serum levels of IFNg, G-CSF, IL-10, and CXCL1 and reduced tumor burden. After demonstrating IL-15 expression in human colorectal cancer (CRC) cells in situ, we investigated the role of this cytokine in the modulation of key colonic oncogenic pathways in the tumor. While these pathways were found to be unaltered in the absence of IL-15, tumor transcriptome analysis showed that the loss of IL-15 upregulates key inflammatory mediators associated with colon cancer progression, such as IL-1b, IL-22, IL-23, Cxcl5, and Spp1. These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of antitumor cytotoxicity, and modulation of the inflammatory tumor micromilieu.

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Section: Discussionmentioning

confidence: 74%

IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

et al. 2015

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“…Another possibility is that low HBZ expression in the tumor could indicate that HBZ is indirectly effecting tumor formation through inflammation or other signaling pathways. Inflammation has been reported to increase tumor formation and loss of IL-15 promoted tumor development in the Granzyme B Tax model [ 33 ]. Importantly, the CD4-HBZ transgenic model also reported systemic inflammation that contributed to leukemia onset [ 21 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice

et al. 2017

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Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy that occurs in HTLV-1 infected patients. Most ATL patients develop osteolytic lesions and hypercalcemia of malignancy, causing severe skeletal related complications and reduced overall survival. The HTLV-1 virus encodes 2 viral oncogenes, Tax and HBZ. Tax, a transcriptional activator, is critical to ATL development, and has been implicated in pathologic osteolysis. HBZ, HTLV-1 basic leucine zipper transcription factor, promotes tumor cell proliferation and disrupts Wnt pathway modulators; however, its role in ATL induced osteolytic bone loss is unknown. To determine if HBZ is sufficient for the development of bone loss, we established a transgenic Granzyme B HBZ (Gzmb-HBZ) mouse model. Lymphoproliferative disease including tumors, enlarged spleens and/or abnormal white cell counts developed in two-thirds of Gzmb-HBZ mice at 18 months. HBZ positive cells were detected in tumors, spleen and bone marrow. Importantly, pathologic bone loss and hypercalcemia were present at 18 months. Bone-acting factors were present in serum and RANKL, PTHrP and DKK1, key mediators of hypercalcemia and bone loss, were upregulated in Gzmb-HBZ T cells. These data demonstrate that Gzmb-HBZ mice model ATL bone disease and express factors that are current therapeutic targets for metastatic and bone resident tumors.

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“…IL-15-deficient HER2/neu transgenic mice showed an earlier mammary carcinogenesis, with median latency time of tumor onset 4 weeks before that of IL-15-proficient NeuT mice, suggesting a role for IL-15 in tumor immunosurveillance. A potential role of IL-15 in tumor immunosurveillance has also recently been reported in a mouse model of lymphoma [ 21 ]. The above-mentioned immune defects, occurring downstream of IL-15 deficiency, might be at the basis of the decreased immunosurveillance of mammary carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis

et al. 2015

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IntroductionWe previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine. Since IL-12 can induce the release of interleukin-15 (IL-15), in the present study we investigated the role played by IL-15 in HER2/neu driven mammary carcinogenesis and in its immunoprevention.MethodsHER2/neu transgenic mice with homozygous knockout of IL-15 (here referred to as IL15KO/NeuT mice) were compared to IL-15 wild-type HER2/neu transgenic mice (NeuT) regarding mammary carcinogenesis, profile of peripheral blood lymphocytes and splenocytes and humoral and cellular responses induced by the vaccine.ResultsIL15KO/NeuT mice showed a significantly earlier mammary cancer onset than NeuT mice, with median latency times of 16 and 20 weeks respectively, suggesting a role for IL-15 in cancer immunosurveillance. Natural killer (NK) and CD8+ lymphocytes were significantly lower in IL15KO/NeuT mice compared to mice with wild-type IL-15. The IL-12-adjuvanted allogeneic HER2/neu-expressing cell vaccine was still able to delay mammary cancer onset but efficacy in IL-15-lacking mice vanished earlier: all vaccinated IL15KO/NeuT mice developed tumors within 80 weeks of age (median latency of 53 weeks), whereas more than 70 % of vaccinated NeuT mice remained tumor-free up to 80 weeks of age. Vaccinated IL15KO/NeuT mice showed less necrotic tumors with fewer CD3+ lymphocyes and lacked perforin-positive infiltrating cells compared to NeuT mice. Concerning the anti-vaccine antibody response, antibody titer was unaffected by the lack of IL-15, but less antibodies of IgM and IgG1 isotypes were found in IL15KO/NeuT mice. A lower induction by vaccine of systemic interferon-gamma (IFN-γ) and interleukin-5 (IL-5) was also observed in IL15KO/NeuT mice when compared to NeuT mice. Finally, we found a lower level of CD8+ memory cells in the peripheral blood of vaccinated IL15KO/NeuT mice compared to NeuT mice.ConclusionsWe demonstrated that IL-15 has a role in mammary cancer immunosurveillance and that IL-15-regulated NK and CD8+ memory cells play a role in long-lasting immunoprevention, further supporting the potential use of IL-15 as adjuvant in immunological strategies against tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0588-x) contains supplementary material, which is available to authorized users.

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IL-15 Deficient Tax Mice Reveal a Role for IL-1α in Tumor Immunity

Cited by 10 publications

References 48 publications

IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice

Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis

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