Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

Stromnes, Ingunn M.; Blattman, Joseph N.; Tan, Xiaoxia; Jeevanjee, Sara; Gu, Hua; Greenberg, Philip D.

doi:10.1172/jci41991

Cited by 74 publications

(69 citation statements)

References 60 publications

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“…Similarly, Cbl-b −/− mice and T cells lacking Cbl-b demonstrate improved control of subcutaneously implanted tumors (23) and disseminated leukemia (32), along with decreased spontaneous tumor formation in ATM −/− mice (23) and ultraviolet B-treated mice (24). However, tumor phenotypes in DGKζ −/− or Cbl-b −/− mice have not been directly compared.…”

Section: Resultsmentioning

confidence: 99%

Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance

Wesley

McAllister

et al. 2018

ImmunoHorizons

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Targeting negative regulators downstream of the T cell receptor (TCR) represents a novel strategy to improve cancer immunotherapy. Two proteins that serve as critical inhibitory regulators downstream of the TCR are diacylglycerol kinase ζ (DGKζ), a regulator of Ras and PKC-θ signaling, and Casitas b-lineage proto-oncogene b (Cbl-b), an E3 ubiquitin ligase that predominantly regulates PI(3)K signaling. We sought to compare the signaling and functional effects that result from deletion of DGKζ, Cbl-b, or both (double knockout, DKO) in T cells, and to evaluate tumor responses generated in a clinically relevant orthotopic pancreatic tumor model. We found that whereas deletion of Cbl-b primarily served to enhance NF-κB signaling, deletion of DGKζ enhanced TCR-mediated signal transduction downstream of Ras/Erk and NF-κB. Deletion of DGKζ or Cbl-b comparably enhanced CD8+ T cell functional responses, such as proliferation, production of IFNγ, and generation of granzyme B when compared with WT T cells. DKO T cells demonstrated enhanced function above that observed with single knockout T cells after weak, but not strong, stimulation. Deletion of DGKζ, but not Cbl-b, however, resulted in significant increases in numbers of activated (CD44hi) CD8+ T cells in both non-treated and tumor-bearing mice. DGKζ-deficient mice also had enhanced control of pancreatic tumor cell growth compared to Cbl-b-deficient mice. This represents the first direct comparison between mice of these genotypes and suggests that T cell immunotherapies may be better improved by targeting TCR signaling molecules that are regulated by DGKζ as opposed to molecules regulated by Cbl-b.

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Section: Resultsmentioning

confidence: 99%

Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance

Wesley

McAllister

et al. 2018

ImmunoHorizons

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“…A larger number of samples would likely be needed to identify gene-expression patterns associated with clinical outcomes. Of note, several negative regulators of cell function were overexpressed in persisting lymphocytes, including FOXP1, 23 CBL-B, [24][25][26] 14 HVEM can be a ligand for inhibitory or stimulatory receptors expressed in T cells 15,16 and has been described as a mechanism of inhibition induced by regulatory T cells. 35 Its role as a ligand is particularly relevant in the immune response against melanoma tumors, which express HVEM at high frequency.…”

Section: Discussionmentioning

confidence: 99%

Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes

Abate-Daga

Hanada

Davis

et al. 2013

Blood

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Key Points• Gene expression in TCRengineered cells resembles that of virus-reactive cells more than native tumor antigen-reactive cells.• Persisting TCR gene-engineered T cells are sensitive to PD-L1-PD-1 interaction but CD160-associated impairment is ligand-independent.Despite significant progress in the development of adoptive cell-transfer therapies (ACTs) using gene-engineered T cells, little is known about the fate of cells following infusion. To address that, we performed a comparative analysis of gene expression between T-cell receptor-engineered lymphocytes persisting in the circulation 1 month after administration and the product that was infused. We observed that 156 genes related to immune function were differentially expressed, including underexpression of stimulators of lymphocyte function and overexpression of inhibitory genes in postinfusion cells. Of genes overexpressed postinfusion, the product of programmed cell death 1 (PDCD1), coinhibitory receptor PD-1, was expressed at a higher percentage in postinfusion lymphocytes than in the infusion product. This was associated with a higher sensitivity to inhibition of cytokine production by interaction with its ligand PD-L1. Coinhibitory receptor CD160 was also overexpressed in persisting cells, and its expression was associated with decreased reactivity, which surprisingly was found to be ligand-independent. These results contribute to a deeper understanding of the properties of transgenic lymphocytes used to treat human malignancies and may provide a rationale for the development of combination therapies as a method to improve ACT. This trial was registered at www.clinicaltrials.gov as #NCT00509288, #NCT00923195, and

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“…The inhibition of Cbl-b function (either genetically or by small molecular inhibitors) would be another approach to activate the costimulatory pathway for antitumor benefit. Indeed, Stromness et al demonstrated that RNAi mediated knockdown of Cbl-b in effector CD8+ T-cells improved the anti-leukemia efficacy of these cells in a mouse model of adoptive transfer of T-cells (66). The benefit of developing Cbl-b inhibitors would be the combined effects of increasing both adaptive (T-cell) and innate (NK cell) antitumor activity.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Cbl Proteins in Tumorigenesis and Antitumor Immunity—Opportunities for Cancer Treatment

Liyasova

Lipkowitz

2015

Clinical Cancer Research

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The Cbl proteins are a family of ubiquitin ligases (E3s) that regulate signaling through many tyrosine kinase dependent pathways. A predominant function is to negatively regulate receptor tyrosine kinase (RTK) signaling by ubiquitination of active RTKs, targeting them for trafficking to the lysosome for degradation. Also, Cbl-mediated ubiquitination can regulate signaling protein function by altered cellular localization of proteins without degradation. In addition to their role as E3s, Cbl proteins play a positive role in signaling by acting as adaptor proteins which can recruit signaling molecules to the active RTKs. Cbl-b, a second family member, negatively regulates the costimulatory pathway of CD8 T-cells and also negatively regulates Natural Killer (NK) cell function. The different functions of Cbl proteins, and their roles both in the development of cancer and the regulation of immune responses provide multiple therapeutic opportunities. Mutations in Cbl which inactivate the negative E3 function while maintaining the positive adaptor function have been described in approximately 5% of myeloid neoplasms. Understanding how the signaling pathways (e.g. Fms-like tyrosine kinase 3 (Flt3), PI-3 kinase, and signal transducer and activator of transcription (Stat)) are dysregulated by these mutations in Cbl has identified potential targets for therapy of myeloid neoplasms. Conversely, the loss of Cbl-b leads to increased adaptive and innate antitumor immunity suggesting that inhibiting Cbl-b may be a means to increase antitumor immunity across a wide variety of tumors. Thus, targeting the pathways regulated by Cbl proteins may provide attractive opportunities for treating cancer.

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Abrogating Cbl-b in effector CD8+ T cells improves the efficacy of adoptive therapy of leukemia in mice

Cited by 74 publications

References 60 publications

Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance

Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance

Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes

Molecular Pathways: Cbl Proteins in Tumorigenesis and Antitumor Immunity—Opportunities for Cancer Treatment

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