PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression

Dong, Shuai; Harrington, Bonnie K.; Hu, Eileen; Greene, Joseph T.; Lehman, Amy; Tran, Minh; Wasmuth, Ronni; Long, Meixiao; Muthusamy, Natarajan; Brown, Jennifer R.; Johnson, Amy J.; Byrd, John C.

doi:10.1172/jci99386

Cited by 42 publications

(27 citation statements)

References 86 publications

(140 reference statements)

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“…Recently, the adoptive transplantation of murine CLL cells in immunocompetent mice, which significantly accelerates the CLL course in recipients compared to the Eµ-TCL1 transgenic mice, is increasingly used, particularly in studies involving the CLL tumor microenvironment [ 14 , 17 , 18 , 19 ]. To determine if the sex difference in Eµ-TCL1 tg/wt mice can also be observed in the adoptive transfer setting, we performed sequential transplantation of Eµ-TCL1 tg/wt leukemia cells in syngeneic, immunocompetent recipient mice.…”

Section: Resultsmentioning

confidence: 99%

Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

Koch

Reinartz

Saggau

et al. 2020

Cancers

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The Eµ-TCL1 transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individual Eµ-TCL1 transgenic mice and discovered a significantly accelerated disease progression in females compared to males. This difference is also reflected in an aggressive CLL mouse model with additional deletion of Tp53 besides the TCL1 transgene. Moreover, after serial adoptive transplantation of murine CLL cells, female recipients also succumbed to CLL earlier than male recipients. This sex-related disparity in the murine models is markedly contradictory to the human CLL condition. Thus, due to our observation we urge both careful consideration in the experimental design and accurate description of the Eµ-TCL1 transgenic cohorts in future studies.

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Section: Resultsmentioning

confidence: 99%

Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

Koch

Reinartz

Saggau

et al. 2020

Cancers

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“…Thus, targeted disruption of p110δ in Tregs has been shown to promote the regression of solid tumors in mice 73 . In addition, more recent studies have shown that relatively preferential inhibition of Treg function or expansion by p110δ inhibition in vivo may promote the anti-tumor response to solid or liquid tumors 40 , 74 – 77 . However, the interplay between PI3K inhibition and efficacy of other, now standard, immunotherapy agents (e.g.…”

Section: Modulation Of Pi3k To Improve Efficacy Of Immunotherapymentioning

confidence: 99%

Control of T lymphocyte fate decisions by PI3K signaling

Murter

Kane

2020

F1000Res

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Virtually all aspects of T and B lymphocyte development, homeostasis, activation, and effector function are impacted by the interaction of their clonally distributed antigen receptors with antigens encountered in their respective environments. Antigen receptors mediate their effects by modulating intracellular signaling pathways that ultimately impinge on the cytoskeleton, bioenergetic pathways, transcription, and translation. Although these signaling pathways are rather well described at this point, especially those steps that are most receptor-proximal, how such pathways contribute to more quantitative aspects of lymphocyte function is still being elucidated. One of the signaling pathways that appears to be involved in this “tuning” process is controlled by the lipid kinase PI3K. Here we review recent key findings regarding both the triggering/enhancement of PI3K signals (via BCAP and ICOS) as well as their regulation (via PIK3IP1 and PHLPP) and how these signals integrate and determine cellular processes. Lymphocytes display tremendous functional plasticity, adjusting their metabolism and gene expression programs to specific conditions depending on their tissue of residence and the nature of the infectious threat to which they are responding. We give an overview of recent findings that have contributed to this model, with a focus on T cells, including what has been learned from patients with gain-of-function mutations in PI3K as well as lessons from cancer immunotherapy approaches.

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“…Idelalisib is the first PI3K-δ inhibitor to be approved for follicular lymphoma [163] and chronic lymphocytic leukemia [164]. Recently, it has been demonstrated that the selective targeting of the ϒ isoform of PI3K in TAMs modulates the immunosuppressive TME, resulting in tumor regression [165].…”

Section: Targeting the Tme To Counteract Its Tumor-protective Effementioning

confidence: 99%

Formation of the Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It

Aldinucci

Borghese

Casagrande

2019

IJMS

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Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed–Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and “educate” (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

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PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression

Cited by 42 publications

References 86 publications

Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

Control of T lymphocyte fate decisions by PI3K signaling

Formation of the Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It

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