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GSE60977
Homo sapiens
24 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Adoptive cell immunotherapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) can result in complete regression of advanced melanoma in some patients, but the efficacy of this potentially curative therapy is limited by poor persistence of TIL after adoptive-transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in viral-specific murine models, but whether this approach may enhance features of memory (e.g. long-term persistence) in TIL which are characteristically exhausted and senescent is not established. Here we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy for melanoma. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of anti-tumor T cells and improve the efficacy of cellbased immunotherapy for metastatic cancer.
Publication Title
Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer but responses are either short-lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explore potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression but surprisingly did not enhance tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells as previously observed. Instead, we found that the T cell cytokines IFN-gamma and TNF-alpha synergized with vemurafenib to induce cell cycle arrest of tumor cells in vitro. This was recapitulated in vivo as continuous vemurafenib administration was required to delay melanoma progression following ACT. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest have major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer.
Publication Title
Type I cytokines synergize with oncogene inhibition to induce tumor growth arrest.
Sample Metadata Fields
Sex, Disease, Disease stage, Cell line
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
To elucidate the mechanisms by which Nrf2 regulates cell growth, we performed global gene expression profiling of A549 lung cancer cells with knockdown of Nrf2. Gene networks associated with carbohydrate metabolism and drug metabolism were significantly downregulated in Nrf2-depleted A549 cells. Gene Set Enrichment Analysis revealed significant enrichment of genes associated with carbohydrate catabolic processes, positive regulation of metabolic processes, PPP, and arachidonic acid metabolism. In summary, this analysis revealed that Nrf2 positively regulates transcription of genes that play key roles in central carbon metabolism.
Publication Title
Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
We examine the potential of Kras as a metabolic target in lung cancer using the KrasLSL-G12D lung cancer model. We demonstrate that mutant Kras drives a lipogenic gene expression program, and that fatty acid synthesis is important in Kras-induced tumorigenesis.
Publication Title
De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.
Sample Metadata Fields
Specimen part
View Samples