High-throughput sequencing Analysis of mouse BMDM cell Transcriptomes after tumor supernatants induction
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE183634 | GEO | 2024/09/07
REPOSITORIES: GEO
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2016-08-13 | E-GEOD-84996 | biostudies-arrayexpress
Project description:Tumours progress despite being infiltrated by effector T cells. Tumour necrosis is associated with poor survival in a variety of cancers. Here, we report that that necrosis causes release of an intracellular ion, potassium, into the extracellular fluid of human and mouse tumours. Surprisingly, elevated extracellular potassium ([K+]e) was sufficient to profoundly suppress mouse and human T cell anti-tumour function. Elevations in [K+]e acted to acutely impair T cell receptor (TCR) dependent Akt-mTOR phosphorylation and effector function. Potassium mediated suppression of Akt-mTOR signalling and T cell effector function required intact activity of PP2A, a serine/threonine phosphatase. The suppressive effect mediated by elevated [K+]e required a T cell-intrinsic increase in intracellular potassium ([K+]i) and was independent of changes in plasma membrane potential (Vm). Finally, ionic reprogramming of tumour-specific T cells via over-expression of the voltage-gated potassium channel Kv1.3 lowered [K+]i and improved effector functions in vitro and in vivo, with this gain of function being dependent on intact channel function. Consequently, Kv1.3 T cell expression enhanced tumour clearance and the survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint against T cell function within tumours and identify new strategies for cancer immunotherapy.
2016-08-13 | GSE84996 | GEO
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Project description:The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.
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Project description:Here, we reported a novel subset of CD8+ T effectors with transcriptional similarity to central memory CD8+ T cells (Tcm). Such CD8+ T effectors were characterized with abundant surface expression of both Cxcr3 and CD62L and possessed strong stemness. These CD8+ T effectors mainly developed into Tcm in adoptive transfer and exclusively possessed the capacity to generate Tcm in antigen re-stimulation, indicating they functioned to be Tcm precursors. These Cxcr3+CD62L+ Tcm precursors were determined by high expression of T cell transcription factor 1 (TCF-1), which guaranteed CD62L expression by binding to distal enhancers of Sell (gene symbol for CD62L). Cxcr3+CD62L+ Tcm precursors could be massively obtained by expansion of anti-CD3/28 activated CD8+ T cells with low IL-2 plus IL-7, and these in vitro-expanded Cxcr3+CD62L+ Tcm precursors exhibited strong effective in tumor elimination and were better than conventional high IL-2 expanded-CD8+ T effectors for clearance of tumors.
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