Human Breast Carcinoma Cells Express Type II IL-4 Receptors and Are Sensitive to Antitumor Activity of a Chimeric IL-4-Pseudomonas Exotoxin Fusion Protein in vitro and in vivo

Leland, Pamela; Taguchi, Jun; Husain, Syed R.; Kreitman, Robert J.; Pastan, Ira; Puri, Raj K.

doi:10.1007/bf03402112

Cited by 46 publications

(44 citation statements)

References 37 publications

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“…The absence of g c protein indicated that medulloblastoma cell lines express type II IL-4R as do malignant glioma cells. This configuration is similar to that observed on other tumour cells including renal cell carcinoma, AIDS-Kaposi's tumours, head and neck tumours, colon carcinoma, ovarian carcinoma and breast tumour cells (Husain et al, 1997;Kawakami et al, 2000;Kreitman et al, 1994;Leland et al, 2000;Murata et al, 1997b;Puri et al, 1996b).…”

Section: Discussionsupporting

confidence: 85%

“…We have also shown that this cytotoxin is highly active in the regression of established human xenografts in nude mice. Thus far, cpIL4-PE has been tested against epidermoid, GBM, AIDS-KS, and breast tumour models (Husain et al, 1998(Husain et al, , 1999Kreitman et al, 1995b;Leland et al, 2000). Remarkable antitumour activity including complete disappearance of established disease has been observed.…”

Section: Expression Of Il-4 Binding Sites and Il-4 Receptor Chains Inmentioning

confidence: 99%

“…In addition to demonstrating expression of IL-4R on cancer cells including brain tumour cells, we have extensively studied the structure and signal transduction of IL-4R on cancer cells (Kawakami et al, 2000;Leland et al, 2000;Murata et al, 1995Murata et al, , 1997aMurata et al, ,b, 1998aObiri et al, 1993Obiri et al, , 1997. We have shown that the IL-4R exists in three different types (Murata et al, 1995(Murata et al, , 1998a.…”

mentioning

confidence: 99%

“…We have shown that the IL-4R exists in three different types (Murata et al, 1995(Murata et al, , 1998a. Type I (classical) IL-4Rs are composed of IL-4Ra (also known as IL-4Rb) and IL-2Rg chain (g c ), while type II (alternative) receptors are composed of IL-4Ra and IL13Ra1 subunits (Kawakami et al, 2000;Leland et al, 2000;Murata et al, 1995Murata et al, , 1997a. In some cell types all three chains are present .…”

mentioning

confidence: 99%

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IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein

et al. 2002

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Cytotoxins directed to interleukin-4 receptors have shown to mediate relatively selective cytotoxicity against a variety of human cancer cells in vitro and in vivo. In an ongoing Phase I clinical trial, a recombinant protein comprised of circularly permuted IL-4 fused to a mutated form of Pseudomonas exotoxin (the fusion protein termed IL-4(38-37)-PE38KDEL or cpIL4-PE) has shown antitumour activity against malignant glioma. Human medulloblastomas are neuroectodermal tumours that occur in children and have a poor prognosis. The goal of this study was to determine whether human medulloblastoma derived cell lines express interleukin-4 receptor and whether interleukin-4 receptor expression is accompanied by sensitivity to cpIL4-PE. Medulloblastoma cell lines express interleukin-4 receptor at the protein and mRNA levels as determined by binding, indirect immunofluorescence and RT -PCR studies. These cells expressed IL-4Ra (also known as IL-4Rb) and IL-13Ra1 (also known as IL-13Ra') chains, however common g c , a component of the interleukin-4 receptor system in immune cells was not detected. Consistent with the expression of IL-4R, cpIL4-PE was found to be highly and specifically cytotoxic to four of five medulloblastoma cell lines. Susceptibility of medulloblastoma cell lines to cpIL4-PE seemed to correlate closely to the functional IL-4 binding sites in general as demonstrated by 125 I-IL-4 binding, but did not seem to correlate with mRNA or cell surface immunoreactive receptor protein expression. The sensitivity of medulloblastoma cells to cpIL4-PE could be eliminated by concurrent incubation with IL-4 or IL-13, but not with IL-2. None of these cell lines showed any change in proliferation upon treatment with exogenous IL-4. These studies establish the interleukin-4 receptor as a medulloblastoma-associated target for possible tumour-directed cancer therapy. Further studies are warranted to investigate interleukin-4 receptor expression in primary medulloblastoma tumours and sensitivity to cpIL-4PE in vitro and in vivo.

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Section: Discussionsupporting

confidence: 85%

Section: Expression Of Il-4 Binding Sites and Il-4 Receptor Chains Inmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein

et al. 2002

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“…24,28 Thus, these tumors and fibroblasts express type I IL-13R. On the other hand, cancer cells derived from prostate, 29,30 breast, 31 some head and neck, 26,27 and some ovarian cancer 11,24 express type II IL-13R.…”

Section: Introductionmentioning

confidence: 99%

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

Kawakami

Husain

et al. 2003

Gene Ther

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Interleukin-13 receptor (IL-13R) a2 chain plays a key role in ligand binding and internalization. We have recently demonstrated that this cytokine receptor chain has unique characteristics in tumor biology: it inhibits tumorigenicity of breast and pancreatic cancer in animal models. In this study, we have exploited IL-13Ra2 chain and established a novel approach for pancreatic cancer therapy. For this, a plasmid encoding the IL-13Ra2 chain gene was mixed with liposomes and injected into subcutaneously or orthotopically xenografted human pancreatic tumors in immunodeficient mice, followed by systemic or local therapy by a recombinant IL-13 cytotoxin. Only tumors forced to express IL-13Ra2 chain acquired extreme susceptibility to the antitumor effect of IL-13 cytotoxin. There was a dominant infiltration of cells including macrophages and natural killer cells in the regressing tumors. Since macrophages were found to produce nitric oxide, IL-13Ra2-targeted cancer therapy involved not only a direct tumor cell killing by IL-13 cytotoxin but also activation of innate immune response at the tumor site. Therefore, this approach may be a new powerful tool for pancreatic cancer or other localized cancer therapy.

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Therapeutic targeting with DABIL‐4 depletes myeloid suppressor cells in 4T1 triple‐negative breast cancer model

et al. 2021

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In many solid tumors including triple‐negative breast cancer (TNBC), upregulation of the interleukin‐4 receptor (IL‐4R) has been shown to promote cancer cell proliferation, apoptotic resistance, metastatic potential, and a Th2 response in the tumor microenvironment (TME). Since immunosuppressive cells in the TME and spleen including myeloid‐derived suppressor cells (MDSCs) and tumor‐associated macrophages (TAMs) also express the IL‐4R, we hypothesized that selective depletion of IL‐4R‐bearing cells in TNBC would result in the direct killing of tumor cells and the depletion of immunosuppressive cells and lead to an enhanced antitumor response. To selectively target IL‐4R + cells, we employed DABIL‐4, a fusion protein toxin consisting of the catalytic and translocation domains of diphtheria toxin fused to murine IL‐4. As anticipated, DABIL‐4 has potent cytotoxic activity against TNBC cells both in vitro and in vivo . We demonstrate in the murine 4T1 TNBC model that DABIL‐4 significantly reduces tumor growth, splenomegaly, and lung metastases. Importantly, we also show that the administration of DABIL‐4 results in the selective depletion of MDSCs, TAMs, and regulatory T cells in treated mice, with a concomitant increase in IFN‐γ + CD8 effector T cells in the TME. Since the 4T1 antitumor activity of DABIL‐4 was largely diminished in IL‐4R knockout mice, we postulate that DABIL‐4 functions primarily as an immunotherapeutic by the depletion of MDSCs, TAMs, and regulatory T cells. NanoString analysis of control and treated tumors confirmed and extended these observations by showing a marked decline of mRNA transcripts that are associated with tumorigenesis and metastasis. In conclusion, we demonstrate that DABIL‐4 targeting of both tumor and immunosuppressive host cells likely represents a novel and effective treatment strategy for 4T1 TNBC and warrants further study.

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Human Breast Carcinoma Cells Express Type II IL-4 Receptors and Are Sensitive to Antitumor Activity of a Chimeric IL-4-Pseudomonas Exotoxin Fusion Protein in vitro and in vivo

Cited by 46 publications

References 37 publications

IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein

IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

Therapeutic targeting with DABIL‐4 depletes myeloid suppressor cells in 4T1 triple‐negative breast cancer model

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