Transcriptional signatures of tumor infiltrating CAR-T cells
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ABSTRACT:
PROVIDER: PRJNA804552 | ENA |
REPOSITORIES: ENA
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Project description:Study goal is to disclose features of gene expressio profile of non-cancerous liver-infiltrating lymphocytes of type C hepatitis patients with hepatocellular carcinomas and tumor-infiltrating lymphocytes of type C hepatitis patients with hepatocellular carcinomas. Keywords: gene expression profile, non-cancerous liver-infiltrating lymphocytes, tumor-infiltrating lymphocytes, type C hepatitis, hepatocellular carcinoma Non-cancerous liver-infiltrating lymphocytes were obtained by laser capture microdissection from surgically resected liver tissues of 12 type C hepatitis patients with hepatocellular carcinoma. The mRNA was amplified and expression profile was comprehensively analyzed with reference RNA using oligo-DNA chip. Tumor-infiltrating lymphocytes were obtained by laser capture microdissection from surgically resected cancer tissues of 12 type C hepatitis patients with hepatocellular carcinoma. The mRNA was amplified and expression profile was comprehensively analyzed with reference RNA using oligo-DNA chip.
2010-06-25 | E-GEOD-10461 | biostudies-arrayexpress
Project description:Chimeric antigen receptor (CAR) engineering of NK cells is an active area of research with early-phase clinical studies showing an excellent safety profile with encouraging clinical responses. However, the transcriptional signatures that control the fate of CAR-NK cell after infusion and their association with tumor control remain poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) to depict the evolution of various engineered CAR-NK cells from the ex vivo infusion products to the in vivo peak phase of tumor control and finally to the relapse phase. Single cell RNA sequencing (scRNA) has revolutionized high-thoughout systems-based analysis of cellular and functional heterogeneity, and dynamic changes in the immune response during the anti-tumor immune cell therapy . The goals of this work are to compare transcriptome profiling (RNA-seq) from both engrafted tumor cells and infused CAR-NK cells over time of treatment course to evaluate the kenetic of tumor cell response and effector functional change of CAR-NK cell. Our study represents the first detailed transcriptomic analysis of using CAR-NK cell therapy aganist Raji-engrafted mouse model. Collecting samples from different time points and organs, the data analysis reported here should privide an envision of the dynamic about how tumor response to immune cell therapy of using CAR-NK cells and also how immune effector fucntion of CAR-NK cell was modulated over time during the treatment courses.
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Project description:Purpose: High tumor burden prior to CAR T-cell therapy predicts poor outcome, however it is unclear if this is driven more by cell number or underlying biology. It is also unclear if tumor intrinsic properties that confer CAR T-cell resistance can be clinically manipulated to improve response. Here we capitalize on radiation’fering effects by dose in vivo to examine the relative importance of tumor quantity versus quality prior to CAR T-cell therapy. Experimental Design: Using Nalm6 ALL tumor-bearing mice, we investigate the impact of high dose (20Gy in 5 fractions) radiation to focal bulky disease, versus less cytotoxic low-dose (1.8Gy) to all disease (total tumor irradiation; TTI) on CAR T-cell efficacy. We characterize the dynamics of predictive transcriptional states in mice and patients using tumor RNA-seq under conditions of excellent vs poor response. Results: We find the in vivo sensitivity of leukemia cells to CAR T-cells is not only predicted by a transcriptional score, but this score can be temporarily increased by low dose TTI, which is associated with significantly improved survival. Focal high dose radiation (as is currently done clinically) was more debulking but did not improve survival. The tumor transcriptional state induced by low dose radiation was found in >80% of long-term CAR T-cell survivors. Conclusions: These findings provide a path to 1) identify patients unlikely to respond to CAR T_x0002_cells due to potentially reversible tumor-intrinsic resistance, and 2) potentially improve response using low dose TTI to adjust a tumor’s unfavorable transcriptional state prior to CAR T-cell delivery.
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Project description:The study aimed to elucidate the transcriptional changes introduced by genetic engineering of CAR T cells to stably express the homeostatic chemokine receptor CCR7. In vitro killing assays hinted to a higher cytolytic capacity that could be tied to an altered cytoskeletal rearrangement. Human CAR and CAR.CCR7 T cells were generated by retroviral transduction and enriched by FACS at the end of the expansion phase (day 10), either without or with a previous over-night co-culture with target Jeko1 tumor cells that express the CAR target antigen CXCR5. Enriched cells were immediately processed for bulk mRNA Seq
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