IL-27 gene therapy induces depletion of Tregs and enhances the efficacy of cancer immunotherapy

Zhu, Jie; Liu, Jinqing; Shi, Min; Cheng, Xiaojuan; Ding, Miao; Zhang, Jianchao C.; Davis, Jonathan P.; Varikuti, Sanjay; Satoskar, Abhay R.; Lu, Lanchun; Pan, Xueliang; Zheng, Pan; Liu, Yang; Bai, Xue‐Feng

doi:10.1172/jci.insight.98745

Cited by 47 publications

(67 citation statements)

References 55 publications

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“…Therefore, the anti-inflammatory function of IL-27 may occur through action on Tregs, and IL-27induced IL-10 production by conventional Foxp3 2 T cells may not be a major pathway of IL-27 in vivo. Notably, high-dose (∼1 mg) IL-27 delivered by gene therapy for more than 2 wk depletes Tregs and enhances effector T cell functions (16). In contrast, our study with an osmotic pump delivers∼2 ng per hour over a 7-d period, resulting in reduced inflammation and diminished Treg accumulation in the CNS.…”

Section: Il-27 Does Not Induce Il-10 Production In Cd4 T Cells In Vivomentioning

confidence: 82%

Cutting Edge: IL-27 Attenuates Autoimmune Neuroinflammation via Regulatory T Cell/Lag3–Dependent but IL-10–Independent Mechanisms In Vivo

Kim

Nguyen

et al. 2019

The Journal of Immunology

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IL-27 regulates immune responses in inflammation. The underlying mechanism of IL-27 functions has long been attributed to its ability to induce IL-10 production in activated CD4 T cells. In this study, we report that Foxp3+ regulatory T cells (Tregs) are the main target cells of IL-27, mediating its immunoregulatory functions in vivo. Systemically delivered IL-27 efficiently prevents the development of experimental autoimmune encephalomyelitis, an autoimmune inflammation in the CNS. However, it failed to do so upon Treg depletion. IL-27 signaling in Tregs was necessary, as transferring Tregs deficient in IL-27Rα or Lag3, a downstream molecule induced by IL-27, was unable to protect mice from experimental autoimmune encephalomyelitis. IL-27 efficiently induced IL-10 expression in CD4 T cells in vitro; however, we found no evidence supporting IL-27–induced IL-10 induction in CD4 T cells in vivo. Taken together, our results uncover an irreplaceable contribution of Tregs during IL-27–mediated control of inflammation.

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Section: Il-27 Does Not Induce Il-10 Production In Cd4 T Cells In Vivomentioning

confidence: 82%

Cutting Edge: IL-27 Attenuates Autoimmune Neuroinflammation via Regulatory T Cell/Lag3–Dependent but IL-10–Independent Mechanisms In Vivo

Kim

Nguyen

et al. 2019

The Journal of Immunology

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“…C57BL/6, BALB/c, and IL27R −/− mice were purchased from The Jackson Laboratory and were maintained in the animal facilities of the Ohio State University. Stat1 −/− BALB/c mice were described before (Zhu et al, 2018). B16.F10 melanoma cells and plasmacytoma J558 cells were originally obtained from ATCC and used after a few passages in vitro.…”

Section: Mice and Tumor Cellsmentioning

confidence: 99%

“…Production of rAAV-IL-27 has been described previously (Zhu et al, 2018). To establish tumors in mice, indicated numbers of cancer cells were injected into each C57BL6 or BALB/c mouse s.c. in 100 µl of PBS.…”

Section: Treatment Of Mice With Tumors Using Aavmentioning

confidence: 99%

“…of Tregs in peripheral lymphoid organs and tumors (Zhu et al, 2018). To determine if intra-tumoral injection of AAV-IL-27 depletes Tregs, we used flow cytometry to examine Tregs in spleens and tumors from treated mice.…”

Section: Intra-tumoral Administration Of Aav-il-27 Enhances Accumulatmentioning

confidence: 99%

“…The lack of immunogenicity and toxicity make rAAV the vector of choice for human clinical trials (Aalbers et al, 2011). Recently (Zhu et al, 2018), we have produced IL-27-expressing rAAV (AAV-IL-27) that can efficiently produce IL-27 in recipient mice and made the following novel observations. First, AAV-IL-27 significantly inhibits the growth of a broad-spectrum of tumor types in mice.…”

Section: Introductionmentioning

confidence: 99%

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Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy

Ding

Zhu

et al. 2020

Front. Cell Dev. Biol.

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IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adenoassociated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety of mouse tumor models. A potential caveat of systemic delivery of IL-27 using rAAV is that there is no practical method to terminate IL-27 production when its biological activity is no longer needed. Therefore, in this work, we tested if directly injecting AAV-IL-27 into tumors could lead to similar anti-tumor effect yet avoiding uncontrolled IL-27 production. We found that high levels of IL-27 was produced in tumors and released to peripheral blood after AAV-IL-27 intratumoral injection. AAV-IL-27 local therapy showed potent anti-tumor activity in mice bearing plasmacytoma J558 tumors and modest anti-tumor activity in mice bearing B16.F10 tumors. Intra-tumoral injection of AAV-IL-27 induced infiltration of immune effectors including CD8 + T cells and NK cells into tumors, caused systemic reduction of Tregs and stimulated protective immunity. Mechanistically, we found that IL-27 induced T cell expression of CXCR3 in an IL-27R-dependent manner. Additionally, we found that AAV-IL-27 local therapy had significant synergy with anti-PD-1 or T cell adoptive transfer therapy. Importantly, in mice whose tumors were completely rejected, IL-27 serum levels were significantly reduced or diminished. Thus, intra-tumoral injection of AAV-IL-27 is a feasible approach that can be used alone and in combination with anti-PD-1 antibody or T cell adoptive transfer for the treatment of cancer.

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Cytokines, Interferons, and Hematopoietic Growth Factors

Epperla¹,

Hanel²,

Talpaz³

2022

Holland‐Frei Cancer Medicine

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Overview Cytokines are a diverse family of signaling molecules encompassing interleukins, interferons, and hematopoietic growth factors. As important mediators of immune responses, cytokines play critical roles and have clinical relevance in cancer. Interleukins have numerous diverse effects in cancer, including influencing the growth, differentiation, or survival of endothelial cells; attracting inflammatory cell types or induce secondary cytokines to regulate angiogenesis; influencing the tumor environment and infiltrating hematopoietic effector cells; inhibiting or stimulating tumor growth; and regulating immune responses. Various immunostimulatory cytokines, including ILs, are administered to patients in an attempt to initiate or augment antitumor immune responses. Interferons are a large family of multifunctional secreted proteins involved in antiviral defense, cell growth regulation, and immune activation. The three types of IFNs, types I, II, and III, signal via specific cell surface receptors and the JAK‐STAT pathway to transcriptionally activate IFN‐regulated genes (IRGs). Alterations in IRG expression result in modulation of receptors for other cytokines, concentration of regulatory proteins on the surface of immune effector cells, and activation of enzymes that control cellular growth and function. Both natural and recombinant IFNs have shown antitumor activity as single agents in more than a dozen malignancies. Hematopoietic growth factors, most notably epoetin, thrombopoietin, and granulocyte colony‐stimulating factor (G‐CSF), are used in the clinic to stimulate the growth and differentiation of red blood cells, platelets, or neutrophils in clinical settings including after chemotherapy or bone marrow transplantation in a restorative role.

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IL-27 gene therapy induces depletion of Tregs and enhances the efficacy of cancer immunotherapy

Cited by 47 publications

References 55 publications

Cutting Edge: IL-27 Attenuates Autoimmune Neuroinflammation via Regulatory T Cell/Lag3–Dependent but IL-10–Independent Mechanisms In Vivo

Cutting Edge: IL-27 Attenuates Autoimmune Neuroinflammation via Regulatory T Cell/Lag3–Dependent but IL-10–Independent Mechanisms In Vivo

Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy

Cytokines, Interferons, and Hematopoietic Growth Factors

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