The Absence or Overexpression of IL-15 Drastically Alters Breast Cancer Metastasis via Effects on NK Cells, CD4 T Cells, and Macrophages

Gillgrass, Amy; Gill, Navkiran; Babian, Artem; Ashkar, Ali A.

doi:10.4049/jimmunol.1303175

Cited by 38 publications

(32 citation statements)

References 52 publications

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“…In tumor transplantation model Gillgrass and colleagues recently demonstrated that Il15 ¡/¡ CD4 C T cells display a Th2 phenotype, which may be capable of polarizing macrophages to a pro-metastatic M2 phenotype while lung macrophages of Il15tg mice produce high levels of nitric oxide and IL-12, indicative of an anti-metastatic M1 polarized phenotype. 43,44 The increased tumorgenesis in Il15 ¡/¡ mice was found to be accompanied by increased levels of specific cytokines in serum, among them, IL-17, IFNg and IL-10. TH17 cytokines are expressed by TH17 cells and by innate lymphoid cells (ILCs) in response to IL-23 in the inflamed colon, 45 furthermore IL-17 has been described to promote angiogenesis and tumor growth 46 while IL-22 plays a dual protective and pro-inflammatory role in intestinal inflammation.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2015

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“…administration of F-PLP/pIL15 generated higher IL15 expression levels in both ascites and the serum. This increased localized expression of IL-15 in the tumor microenvironment (ascites) could enhance antitumoral T-cell responses, while the increased serum levels may aid in the prevention of metastasis, thus jointly inhibiting tumor growth [28]. …”

Section: Resultsmentioning

confidence: 99%

A folate receptor-targeted lipoplex delivering interleukin-15 gene for colon cancer immunotherapy

et al. 2016

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Interleukin-15 has been implicated as a promising cytokine for cancer immunotherapy, while folate receptor α (FRα) has been shown to be a potentially useful target for colon cancer therapy. Herein, we developed F-PLP/pIL15, a FRα-targeted lipoplex loading recombinant interleukin-15 plasmid (pIL15) and studied its antitumor effects in vivo using a CT26 colon cancer mouse model. Compared with control (normal saline) treatment, F-PLP/pIL15 significantly suppressed tumor growth in regard to tumor weight (P < 0.001) and reduced tumor nodule formation (P < 0.001). Moreover, when compared to other lipoplex-treated mice, F-PLP/pIL15-treated mice showed higher levels of IL15 secreted in the serum (P < 0.001) and ascites (P < 0.01). These results suggested that the targeted delivery of IL15 gene might be associated with its in vivo antitumor effects, which include inducing tumor cell apoptosis, inhibiting tumor proliferation and promoting the activation of immune cells such as T cells and natural killer cells. Furthermore, hematoxylin and eosin staining of vital organs following F-PLP/pIL15 treatment showed no detectable toxicity, thus indicating that intraperitoneal administration may be a viable route of delivery. Overall, these results suggest that F-PLP/pIL15 may serve as a potential targeting preparation for colon cancer therapy.

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“…First, the local instillation of T cell-recruiting factors (such as recombinant IFN-α2β or CXCL10) might be useful for the treatment of tumors that are defective in type I IFN signaling pathways 15 . Second, defects in MHC class I expression might be reverted (for instance, by the systemic administration of recombinant IFN-α2β or by the local provision of TLR agonists) or functionally bypassed (for instance, by using bispecific antibodies to target T cells to BCAAs or by using IL-15 to boost the cytotoxicity of NK cells, which are considered to be the main gatekeepers of MHC class I-deficient tumors) 132 . Third, exome sequencing may be used to detect mutations yielding potentially immunogenic BCAAs, which would open up the possibility of creating highly personalized peptide-based vaccines 133 .…”

Section: Discussionmentioning

confidence: 99%

Natural and therapy-induced immunosurveillance in breast cancer

Kroemer

Senovilla

Galluzzi

et al. 2015

Nat Med

270

199

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The immunosurveillance theory postulates that tumors evolve and progress in an uncontrolled fashion only when anticancer immune responses fail. Natural immunosurveillance clearly influences human breast cancer (BC) progression because the prognosis of BC patients is dictated by the density, composition and activity of the tumor immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapeutic regimens commonly employed for the treatment of BC affect the tumor immune infiltrate, and accumulating data suggest that the clinical efficacy of these treatments is largely determined by T cell-dependent tumor-specific immune responses. In addition, the mechanism of action of targeted anticancer therapeutics, such as the erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeting agent trastuzumab, involves the innate and adaptive arms of the immune system. In this Review, we discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of BC. Moreover, we point out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.

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The Absence or Overexpression of IL-15 Drastically Alters Breast Cancer Metastasis via Effects on NK Cells, CD4 T Cells, and Macrophages

Cited by 38 publications

References 52 publications

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

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

A folate receptor-targeted lipoplex delivering interleukin-15 gene for colon cancer immunotherapy

Natural and therapy-induced immunosurveillance in breast cancer

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