Biological effects of IL-15 on immune cells and its potential for the treatment of cancer

Zhang, Shuling; Zhao, Jianwen; Bai, Xueli; Handley, Mike; Shan, Fengping

doi:10.1016/j.intimp.2020.107318

Cited by 32 publications

(29 citation statements)

References 142 publications

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“…Post-conditioning increases in IL-15 plasma concentration have been identified as an important factor affecting CAR-T cell expansion, anti-tumor activity and toxicities including ICANS ( 43 ) and CRS ( 44 ). The relevance of IL-15 in anti-tumor immune response, CAR-T cell activation and differentiation into persisting T cell subsets is increasingly recognized ( 45 , 46 ). Our finding of higher pre-conditioning plasma concentrations of IL-15 in patients experiencing CRS could have clinical relevance and highlights the influence of patient – specific factors in the development of toxicities as well as a specific cytokine response.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic Tocilizumab Prior to Anti-CD19 CAR-T Cell Therapy for Non-Hodgkin Lymphoma

et al. 2021

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Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed/refractory lymphomas. Cytokine release syndrome (CRS) and immune effector cell – associated neurotoxicity syndrome (ICANS) are well-known complications. Tocilizumab, a monoclonal antibody targeting the interleukin-6 (IL-6) receptor was administered 1 hour prior to infusion of anti-CD19 CAR-T cells with CD3ζ/4-1BB costimulatory signaling used to treat non-Hodgkin lymphoma patients. Relapsed/refractory lymphoma patients treated with anti-CD19 CAR-T cells were included in this analysis. Cytokine plasma levels were measured by electrochemiluminescence before lymphodepleting chemotherapy, prior to infusion and then on days 2, 4,6, and 14 days after treatment. Twenty patients were treated. Cell products included locally manufactured anti-CD19 CAR-T (n=18) and tisagenlecleucel (n=2). There were no adverse events attributed to tocilizumab. Ten patients had grade 1–2 CRS at a median of 4 (range 3-7) days. There were no cases of grade ≥3 CRS. Five patients had ICANS, grade 1 (n=4) and grade 4 (n=1). Laboratory studies obtained prior to lymphodepleting chemotherapy were comparable between patients with and without CRS, except for interleukin (IL)-15 plasma concentrations. patients with CRS had higher post-infusion ferritin and C reactive protein, with more marked increases in inflammatory cytokines, including IL-6, IL-15, IFN-γ, fractalkine and MCP-1. Fifteen patients (75%) achieved CR and 2 (10%), PR. One-year OS and PFS estimates were 83% and 73%. Prophylactic tocilizumab was associated with low CRS incidence and severity. There were no adverse events associated with tocilizumab, no increase in frequency or severity of ICANS and excellent disease control and overall survival.

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Section: Discussionmentioning

confidence: 99%

Prophylactic Tocilizumab Prior to Anti-CD19 CAR-T Cell Therapy for Non-Hodgkin Lymphoma

et al. 2021

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“…IL-15 is a proinflammatory cytokine involved in the development, proliferation, and activation of several lymphocyte lineages ( 74 ). This cytokine acts as a pleiotropic lymphokine that is not expressed in T cells but is derived from many other cells and tissues, including skeletal tissue, muscle, placenta, lung, kidney, heart, epithelial cells, fibroblasts, and monocytes ( 75 ). IL-15 belongs to the common cytokine receptor common gamma chain (γ c) family of cytokines (with IL-2, IL-4, IL-7, IL-9, and IL-21), playing essential roles in innate and adaptive immunity.…”

Section: Discussionmentioning

confidence: 99%

“…IL-15 can suppress the IL-2-mediated T cell responses and Fas-mediated activation-induced cell death (AICD) process. In contrast to IL-2, IL-15 has little effect on Treg activity, but it can compromise Treg function by acting on CD4+T and CD8+T cells ( 75 ). IL-15 can boost both Th1 responses by enhancing IFN-γ and TNF-α production and Th2 responses by enhancing IL-4 and IL-5 release ( 75 , 77 ).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to IL-2, IL-15 has little effect on Treg activity, but it can compromise Treg function by acting on CD4+T and CD8+T cells ( 75 ). IL-15 can boost both Th1 responses by enhancing IFN-γ and TNF-α production and Th2 responses by enhancing IL-4 and IL-5 release ( 75 , 77 ). Studies have revealed that IL-15 might play a role in resisting intracellular protozoan infections, including Leishmania braziliensis, Cryptosporidium, Plasmodium , and Toxoplasma gondii , by influencing Th1 or Th2 response development ( 77 – 81 ).…”

Section: Discussionmentioning

confidence: 99%

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Immune pathogenesis in pigeons during experimental Prohemistomum vivax infection

et al. 2022

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Prohemistomum vivax is a small trematode belonging to the family Cyathocotylidae, infecting fish-eating birds and mammals, including humans. However, no data on molecular identification and immune pathogenesis are available, challenging effective diagnostic and therapeutic interventions. Here, we identified P. vivax based on combined morphological and molecular data and examined histopathological lesions and the differential cytokines expression in experimentally infected pigeons. Pigeons were orally infected with 500 prohemistomid metacercariae. Intestinal and spleen tissues were harvested 2, 4, 7, 14, 21, and 28 days post-infection (dpi). Gene expression levels of eleven cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-15, IL-18, IFN-γ, and TGF-β3) were assessed using quantitative reverse-transcription PCR (RT-qPCR). We identified the recovered flukes as Prohemistomum vivax based on morphological features and the sequence and phylogenetic analysis of the internal transcribed spacer 1 (ITS1), 5.8 ribosomal RNA, and ITS2 region. Histopathological lesions were induced as early as 2 dpi, with the intensity of villi atrophy and inflammatory cell infiltration increasing as the infection progressed. An early immunosuppressive state (2 and 4 dpi), with TGF-β3 overexpression, developed to allow parasite colonization. A mixed Th1/Th2 immune response (overexpressed IFN-γ, IL-12, IL-2, IL-4, and IL-5) was activated as the infection progressed from 7 to 28 dpi. Inflammatory cytokines (IL-1, IL-6, IL-18, and IL-15) were generally overexpressed at 7–28 dpi, peaking at 7 or 14 dpi. The upregulated Treg IL-10 expression peaking between 21 and 28 dpi might promote the Th1/Th2 balance and immune homeostasis to protect the host from excessive tissue pathology and inflammation. The intestine and spleen expressed a significantly different relative quantity of cytokines throughout the infection. To conclude, our results presented distinct cytokine alteration throughout P. vivax infection in pigeons, which may aid in understanding the immune pathogenesis and host defense mechanism against this infection.

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“…It has been reported that IL-15 protects antigenactivated NKTs from suppression by tumor-conditioned hypoxic tumor-associated macrophages [48]. Moreover, IL-15 can expand and activate NK, NKTs, and memory CD8 + T cells in TME, leading to tumor destruction [49]. The positive impacts of IL-15 on NK and T cells, in addition to NKT cells, may account for the greater power of combined NKT and IL-15 in predicting outcome of MYCN-non-amplified NBL.…”

Section: Discussionmentioning

confidence: 99%

Low Expression of IL-15 and NKT in Tumor Microenvironment Predicts Poor Outcome of MYCN-Non-Amplified Neuroblastoma

Liao

Hung

Tung

et al. 2021

JPM

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Immune tumor microenvironment (TME) in neuroblastoma (NBL) contributes to tumor behavior and treatment response. T cells and natural killer (NK) cells have been shown to play important roles in the neuroblastoma TME. However, few reports address the clinical relevance of natural killer T cells (NKTs) and interleukin-15 (IL-15), one of the crucial cytokines controlling the activation and expansion of NK/NKT cells, in NBL. In this study, we examined NKT immunoscores and IL-15 expression in both MYCN-amplified and MYCN-non-amplified NBL to correlate with clinical outcomes such as event-free survival (EFS) and overall survival (OS). From Gene Expression Omnibus (GEO) datasets GSE45480 (n = 643) and GSE49711 (n = 493), we found that NKT immunoscore and IL-15 expression were both significantly lower in MYCN-amplified NBL, and similar results were observed using our clinical NBL samples (n = 53). Moreover, NBL patients (GEO dataset GSE49711 and our clinical samples) with both lower NKT immunoscore and IL-15 expression exhibited decreased EFS and OS regardless of MYCN gene amplification status. Multivariate analysis further showed that the combination of low NKT immunoscore and low IL-15 expression level was an independent prognostic factor for poor EFS and OS in our NBL patients. These findings provide the rationale for the development of strategy to incorporate IL-15 and NKT cell therapy into the treatment regimen for neuroblastoma.

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Biological effects of IL-15 on immune cells and its potential for the treatment of cancer

Cited by 32 publications

References 142 publications

Prophylactic Tocilizumab Prior to Anti-CD19 CAR-T Cell Therapy for Non-Hodgkin Lymphoma

Prophylactic Tocilizumab Prior to Anti-CD19 CAR-T Cell Therapy for Non-Hodgkin Lymphoma

Immune pathogenesis in pigeons during experimental Prohemistomum vivax infection

Low Expression of IL-15 and NKT in Tumor Microenvironment Predicts Poor Outcome of MYCN-Non-Amplified Neuroblastoma

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