In vivo discovery of immunotherapy targets in the tumour microenvironment

Zhou, Penghui; Shaffer, Donald R.; Arias, Diana A. Alvarez; Nakazaki, Yukoh; Pos, Wouter; Torres, Alexis J.; Cremasco, Viviana; Dougan, Stephanie K.; Cowley, Glenn S.; Elpek, Kutlu G.; Brogdon, Jennifer L.; Lamb, John; Turley, Shannon J.; Ploegh, Hidde L.; Root, David E.; Love, J. Christopher; Dranoff, Glenn; Hacohen, Nir; Cantor, Harvey; Wucherpfennig, Kai W.

doi:10.1038/nature12988

Cited by 200 publications

(177 citation statements)

References 46 publications

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“…S3 A and B). Additionally, 1xLacO and WT P14 memory cells were indistinguishable in their expression of cell surface molecules and production of cytokines upon restimulation ( previous studies to facilitate direct viral transduction of T cells (14)(15)(16)(17)(18) + T cells from wild-type mice, but were markedly altered by the other stimulation conditions, particularly with cytokine treatment (Fig. 2A).…”

Section: Significancementioning

confidence: 78%

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Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8 ⁺ T-cell effector differentiation

Godec

Cowley

Barnitz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The differentiation of effector CD8+ T cells is critical for the development of protective responses to pathogens and for effective vaccines. In the first few hours after activation, naive CD8+ T cells initiate a transcriptional program that leads to the formation of effector and memory T cells, but the regulation of this process is poorly understood. Investigating the role of specific transcription factors (TFs) in determining CD8+ effector T-cell fate by gene knockdown with RNAi is challenging because naive T cells are refractory to transduction with viral vectors without extensive ex vivo stimulation, which obscures the earliest events in effector differentiation. To overcome this obstacle, we developed a novel strategy to test the function of genes in naive CD8+ T cells in vivo by creating bone marrow chimera from hematopoietic progenitors transduced with an inducible shRNA construct. Following hematopoietic reconstitution, this approach allowed inducible in vivo gene knockdown in any cell type that developed from this transduced progenitor pool. We demonstrated that lentivirus-transduced progenitor cells could reconstitute normal hematopoiesis and develop into naive CD8+ T cells that were indistinguishable from wild-type naive T cells. This experimental system enabled induction of efficient gene knockdown in vivo without subsequent manipulation. We applied this strategy to show that the TF BATF is essential for initial commitment of naive CD8+ T cells to effector development but becomes dispensable by 72h. This approach makes possible the study of gene function in vivo in unperturbed cells of hematopoietic origin that are refractory to viral transduction.

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Section: Significancementioning

confidence: 78%

“…Viral vectors expressing shRNA molecules have been used to investigate gene function in the immune system (13,(15)(16)(17)20). However, this approach is limited by the inability to deliver viral vectors to quiescent cells.…”

Section: Discussionmentioning

confidence: 99%

Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8 ⁺ T-cell effector differentiation

Godec

Cowley

Barnitz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The present study was aimed at discovering potential genes involved in tumorigenic ability using shRNA screening techniques (14)(15)(16)(23)(24)(25). Previous studies have utilized a pool of less than 1,000 shRNAs as it was difficult to select a single meaningful gene from a large-scale shRNA pool.…”

Section: Discussionmentioning

confidence: 99%

Involvement of DDX6 gene in radio- and chemoresistance in glioblastoma

Cho

Kang

Kim

et al. 2016

International Journal of Oncology

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Abstract. CCRT (concomitant chemotherapy and radiation therapy) is often used for glioblastoma multiforme (GBM) treatment after surgical therapy, however, patients treated with CCRT undergo poor prognosis due to development of treatment resistant recurrence. Many studies have been performed to overcome these problems and to discover genes influencing treatment resistance. To discover potential genes inducing CCRT resistance in GBM, we used whole genome screening by infecting shRNA pool in patient-derived cell. The cells infected ~8,000 shRNAs were implanted in mouse brain and treated RT/TMZ as in CCRT treated patients. We found DDX6 as the candidate gene for treatment resistance after screening and establishing DDX6 knock down cells for functional validation. Using these cells, we confirmed tumor associated ability of DDX6 in vitro and in vivo. Although proliferation improvement was not found, decreased DDX6 influenced upregulated clonogenic ability and resistant response against radiation treatment in vivo and in vitro. Taken together, we suggest that DDX6 discovered by using whole genome screening was responsible for radio-and chemoresistance in GBM.

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“…2). A growing list of such candidates have been described (29,(31)(32)(33)(34)(35)(36)(37). For example, partial inhibition of Blimp-1 in exhausted T cells led to the downregulation of multiple inhibitory receptors and prevented exhaustion (29).…”

Section: Improving On Pd-1 Blockade and Immune Modulationmentioning

confidence: 99%

Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

Gilboa

Berezhnoy

Schrand

2015

Cancer Immunology Research

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Modulating the function of immune receptors with antibodies is ushering in a new era in cancer immunotherapy. With the notable exception of PD-1 blockade used as monotherapy, immune modulation can be associated with significant toxicities that are expected to escalate with the development of increasingly potent immune therapies. A general way to reduce toxicity is to target immune potentiating drugs to the tumor or immune cells of the patient. This Crossroads article discusses a new class of nucleic acid-based immune-modulatory drugs that are targeted to the tumor or to the immune system by conjugation to oligonucleotide aptamer ligands. Cell-free chemically synthesized short oligonucleotide aptamers represent a novel and emerging platform technology for generating ligands with desired specificity that offer exceptional versatility and feasibility in terms of development, manufacture, and conjugation to an oligonucleotide cargo. In proof-of-concept studies, aptamer ligands were used to target immune-modulatory siRNAs or aptamers to induce neoantigens in the tumor cells, limit costimulation to the tumor lesion, or enhance the persistence of vaccine-induced immunity. Using increasingly relevant murine models, the aptamer-targeted immune-modulatory drugs engendered protective antitumor immunity that was superior to that of current "gold-standard" therapies in terms of efficacy and lack of toxicity or reduced toxicity. To overcome immune exhaustion aptamer-targeted siRNA conjugates could be used to downregulate intracellular mediators of exhaustion that integrate signals from multiple inhibitory receptors. Recent advances in aptamer development and second-generation aptamer-drug conjugates suggest that we have only scratched the surface.

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In vivo discovery of immunotherapy targets in the tumour microenvironment

Cited by 200 publications

References 46 publications

Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8 ⁺ T-cell effector differentiation

Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8 ⁺ T-cell effector differentiation

Involvement of DDX6 gene in radio- and chemoresistance in glioblastoma

Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

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In vivo discovery of immunotherapy targets in the tumour microenvironment

Cited by 200 publications

References 46 publications

Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8 + T-cell effector differentiation

Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8 + T-cell effector differentiation

Involvement of DDX6 gene in radio- and chemoresistance in glioblastoma

Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

Contact Info

Product

Resources

About

Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8 ⁺ T-cell effector differentiation

Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8 ⁺ T-cell effector differentiation