Production of Interleukin-2 by EL4 Tumor Cells Induces Natural Killer Cell- and T-Cell-Mediated Immunity

Visseren, M. J. W.; Koot, M.; Voort, Ellen I. H. van der; Gravestein, Loes A.; Schoenmakers, H. J.; Kast, W. Martin; Zijlstra, Maarten; Melief, C. J. M.

doi:10.1097/00002371-199402000-00005

Cited by 15 publications

(7 citation statements)

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“…39,40 This would be consistent with our observations, as T cell and NK cell killing both appear important for resistance to BDL-2 based on our depletion studies of these cell populations. It appears that CD8+ but not CD4+ cells are responsible for resistance of injections of BDL-2 cells systemically.…”

Section: Discussionsupporting

confidence: 91%

Interleukin-2 Secretion by Transduced and Unselected BDL-2 Lymphoma Results in Increased Survival in Mice with Previously Established Disseminated Disease

Orchard¹,

Katsanis²,

Boyer³

et al. 1996

Cancer Biotherapy and Radiopharmaceuticals

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The transfer and expression of cytokine genes into malignant cells to provide a more effective tumor response has shown promise. The majority of murine models in which tumor vaccination strategies have been tested have utilized selected and expanded clones of tumor cells, which is impractical clinically. In a model of murine B lineage lymphoma (BDL-2), we compared the effectiveness of tumor vaccines composed of a) a BDL-2 clone established by G-418 resistance following transduction with the LIL2SN retrovirus and screened for maximal IL-2 secretion, b) a syngeneic fibroblast line transduced with LIL2SN and screened for G-418 resistance and IL-2 expression, which was co-injected with the parental line, and c) a heterogeneous (unselected) population of BDL-2 cells transduced with the MFG/IL2 virus, reported to provide enhanced expression of cytokine genes and minimize the need for selection. Testing of splenocytes derived from vaccinated animals reveals that injections of BDL-2 expressing IL-2 results in an increased capacity of splenocytes to kill BDL-2 in vitro, compared to vaccination of BDL-2 alone or in combination with IL-2 secreting fibroblasts. We show that a vaccine composed of MFG/IL2 transduced, unselected BDL-2 cells is equivalent or superior to a clone derived from LIL2SN transduction in prolonging survival of animals with previously established tumor. These studies provide evidence that transduction of tumor with MFG based vectors without in vitro selection leads to expression of high levels of IL-2 and can impact the survival of animals with disseminated tumor.

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Section: Discussionsupporting

confidence: 91%

Interleukin-2 Secretion by Transduced and Unselected BDL-2 Lymphoma Results in Increased Survival in Mice with Previously Established Disseminated Disease

Orchard¹,

Katsanis²,

Boyer³

et al. 1996

Cancer Biotherapy and Radiopharmaceuticals

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“…Peritoneal macrophages were elicited and co-implanted with B16F10 cells to determine whether a lack of tumor-infiltrating macrophages affected tumor growth. However, the elicited peritoneal macrophages were already activated To determine why APNKO mice respond differently to EL4 and B16F10, we evaluated the IL-2 mRNA expression levels because IL-2-secreting EL4 cells can enhance NK cell-and CTLmediated innate immunity in tumor-bearing hosts (42). IL-2 mRNA expression was not observed in either the EL4 or the B16F10 cells (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Adiponectin Deficiency Suppresses Lymphoma Growth in Mice by Modulating NK Cells, CD8 T Cells, and Myeloid-Derived Suppressor Cells

Han

Jeong

Lee

et al. 2013

The Journal of Immunology

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Previously, we found that adiponectin (APN) suppresses IL-2–induced NK cell activation by downregulating the expression of the IFN-γ–inducible TNF-related apoptosis-inducing ligand and Fas ligand. Although the antitumor function of APN has been reported in several types of solid tumors, with few controversial results, no lymphoma studies have been conducted. In this study, we assessed the role of APN in immune cell function, including NK cells, CTLs, and myeloid-derived suppressor cells, in EL4 and B16F10 tumor-bearing APN knockout (KO) mice. We observed attenuated EL4 growth in the APNKO mice. Increased numbers of splenic NK cells and splenic CTLs were identified under naive conditions and EL4-challenged conditions, respectively. In APNKO mice, splenic NK cells showed enhanced cytotoxicity with and without IL-2 stimulation. Additionally, there were decreased levels of myeloid-derived suppressor cell accumulation in the EL4-bearing APNKO mice. Enforced MHC class I expression on B16F10 cells led to attenuated growth of these tumors in APNKO mice. Thus, our results suggest that EL4 regression in APNKO mice is not only due to an enhanced antitumor immune response but also to a high level of MHC class I expression.

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“…Intercrossing TEL-JAK2 transgenic animals with TCRα -/-mice does not shift disease phenotype or latency (N. dos Santos and J. Ghysdael, personal communication). The situation for EL-4-induced lymphoma is less clear cut, because NK cells as well as CTLs have been reported to lyse EL-4 cells (33)(34)(35).…”

Section: Figurementioning

confidence: 99%

TYK2 is a key regulator of the surveillance of B lymphoid tumors

Stoiber¹,

Kovacic²,

Schuster³

et al. 2004

J. Clin. Invest.

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Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice. We show here that the Janus kinase TYK2 serves an opposite function. Mice deficient in TYK2 developed Abelsoninduced B lymphoid leukemia/lymphoma as well as TEL-JAK2-induced T lymphoid leukemia with a higher incidence and shortened latency compared with WT controls. The cell-autonomous properties of Abelson murine leukemia virus-transformed (A-MuLV-transformed) TYK2 -/-cells were unaltered, but the high susceptibility of TYK2 -/-mice resulted from an impaired tumor surveillance, and accordingly, TYK2 -/-A-MuLV-induced lymphomas were easily rejected after transplantation into WT hosts. The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2 -/-NK and NKT cells toward tumor-derived cells. RAG2/TYK2 double-knockout mice succumbed to A-MuLV-induced leukemia/lymphoma faster than RAG2 -/-TYK2 +/-mice. This defines NK cells as key players in tumor surveillance in Abelson-induced malignancies. Our observations provide compelling evidence that TYK2 is an important regulator of lymphoid tumor surveillance. IntroductionThe JAK-STAT pathway regulates cell proliferation, differentiation, and survival in hematopoietic cells (1, 2). Binding of a cytokine to its cognate receptor activates receptor-associated JAKs which in turn mediate the subsequent tyrosine phosphorylation of STAT proteins. Phosphorylated STAT proteins form dimers, translocate to the nucleus, and bind to specific DNA elements to induce or modulate expression of target genes. Gene knockout studies in mice underlined the vital role of the JAK-STAT pathway for hematopoiesis and other developmental processes (3).Recent interest had focused on the role of the JAK-STAT pathway in tumor formation. Aberrant activation of JAK-STAT signaling had been shown in multiple solid tumors and leukemia (4-9). In particular, STAT3 and STAT5 have drawn much attention; both transcription factors display oncogenic properties when expressed ectopically. A constitutively active mutant of STAT3 was shown to transform rat fibroblasts (10), and the enforced expression of WT STAT5 in the lymphoid lineage induced T cell leukemia in mice (11). In addition, JAK1 has been implicated in transformation by the v-abl as well as by the v-src oncogene (12, 13), and constitutive activation of JAK2 as in the TEL-JAK2 oncogene suffices to induce leukemia in mice and humans (14, 15). On the other hand, JAK1 was shown to be a tumor suppressor downstream of IFN-γ in a B lymphoid tumor model (16). A role as tumor suppressor downstream of IFN-γ has also been attributed to STAT1 (17-21). STAT1 -/-mice have been repeatedly used to study the role of IFN-γ in tumorigenesis and tumor surveillance (18,19). Recent evidence also proposed that STAT1 acted as a tumor suppressor by modulating apoptosis (22).TYK2 has been initially defined as a mediator of IFN-α/β sign...

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Production of Interleukin-2 by EL4 Tumor Cells Induces Natural Killer Cell- and T-Cell-Mediated Immunity

Cited by 15 publications

References 0 publications

Interleukin-2 Secretion by Transduced and Unselected BDL-2 Lymphoma Results in Increased Survival in Mice with Previously Established Disseminated Disease

Interleukin-2 Secretion by Transduced and Unselected BDL-2 Lymphoma Results in Increased Survival in Mice with Previously Established Disseminated Disease

Adiponectin Deficiency Suppresses Lymphoma Growth in Mice by Modulating NK Cells, CD8 T Cells, and Myeloid-Derived Suppressor Cells

TYK2 is a key regulator of the surveillance of B lymphoid tumors

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