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Next Generation Sequencing analysis using splenic cells freshly isolated from Wild Type-OT-I (WT) and OTUB1-CD4Cre-OT-I (KO) mice

ABSTRACT: CD8 T cells play a central role in immune responses against pathogens and cancer; however, CD8 T cells are typically rendered hypofunctional in tumor microenvironment due to tolerance to cancer cells and functional exhaustion. How to overcome CD8 T cell tolerance and stimulate strong antitumor responses has become an important issue for cancer immunotherapy 1,2. Here we identified the atypical deubiquitinase Otub1 as a pivotal regulator of CD8 T cell self-tolerance and antigen-stimulated responses. T cell-specific deletion of Otub1 in mice breaks CD8 T cell self-tolerance and promotes the metabolic reprograming and effector functions of activated CD8 T cells, resulting in profoundly stronger immunity against infections and tumorigenesis. The Otub1 deletion also synergizes with an immune checkpoint inhibitor in inducing tumor rejection and greatly increases the efficiency of an adoptive T cell transfer model of cancer immunotherapy. In line with these findings, the expression level of Otub1 is inversely associated with the abundance of CD8 effector T cell signature gene expression and patient survival in human melanoma. Mechanistically, Otub1 negatively regulates activation of AKT, a kinase that integrates the T cell receptor (TCR) and cytokine signals and mediates CD8 T cell metabolism and effector functions. Otub1 deficiency greatly promotes AKT activation by both the TCR signal and the immunostimulatory cytokine IL-15. Otub1 inhibits AKT ubiquitination and, thereby, suppresses its interaction with the membrane lipid phosphoinositol 3,4,5 triphosphate required for membrane translocation. These results demonstrate a ubiquitin-dependent mechanism that controls CD8 T cell responses and implicate Otub1 as a potential therapeutic target for cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE126777 | GEO | 2019/05/16

REPOSITORIES: GEO

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Project description:The optimal T cell attributes for the adoptive immunotherapy of cancer and viral diseases are currently unclear. Recent adoptive transfer clinical trials using ex vivo expanded tumor infiltrating lymphocytes has provided evidence that differentiated effector T cells can mediate durable responses in selected cancer patients. The capacity of these transferred cells to persist in the host was found to strongly correlate with their clinical activity. Thus, there is significant interest in identifying intrinsic markers that define antigen specific effector T cells that can develop into long-lived memory cells rather than undergoing apoptosis after infusion in humans. We recently reported the long term persistence of ex vivo expanded tumor specific CD8+ T effector clones in refractory metastatic melanoma patients after adoptive T cell transfer. By utilizing these highly homogeneous clone populations, we sought to define the pre-infusion cellular and molecular attributes associated with their effector to memory transition. Comparative transcriptional profiling found the pre-infusion clone mRNA expression levels of the IL-7 receptor (IL-7Ra) and the proto-oncogene, c-myc, directly correlated with the level of clonal persistence after adoptive transfer in humans. The predictive value of these markers was further established by utilizing IL-7R protein, induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor specific effector clones that could engraft after controlled adoptive transfer into highly immunodeficient mice. These findings support that IL-7R and c-myc expression are valuable cell intrinsic markers that can predict the fate of effector CD8+ T cells after adoptive transfer. We used microarrays to compare the pre-infusion gene expression profile of melanoma-specific CD8+ T cell clones that would eventually either persist or not after adoptive transfer in humans. We derived ten melanoma-specific CD8+ T cell clones and determined their degree of persistence after adoptive therapy into patients. We performed microarray on the pre-infusion samples of six persisting and four non-persisting clones to obtain a comparative gene signature profile.

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Next Generation Sequencing analysis using splenic cells freshly isolated from Wild Type-OT-I (WT) and OTUB1-CD4Cre-OT-I (KO) mice

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