Two-Stage CAR T-Cell Differentiation in Patients with Large B-Cell Lymphoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA854096 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19899400.fastq.gz | Fastqsanger.gz | |||
| SRR19899401.fastq.gz | Fastqsanger.gz | |||
| SRR19899402.fastq.gz | Fastqsanger.gz | |||
| SRR19899403.fastq.gz | Fastqsanger.gz | |||
| SRR19899404.fastq.gz | Fastqsanger.gz |
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Project description:<p>Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (r/r) large B-cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether a MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme which regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers which resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine and lysophospholipids which was validated in an independent set from another institution as predictive of non-durable response to CAR T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL. </p>
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Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
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Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
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Project description:Purpose: To compare cell states amoung three populations of interest among circulating CAR T cells in patients with lymphoma. Methods: Nine patients with large B-cell lymphoma (LBCL) were treated with axicabtagene ciloleucel (axi-cel), a commercial CD19-targeted CAR T-cell therapy. On day 7, fresh peripheral blood mononuclear cells were stained with an antibody panel for fluorescence-activated cell sorting (FACS), a panel for cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), and a viability dye. Single live CAR+ T cells were sorted from each patient, counted, processed for 5' single-cell RNA-sequencing with feature barcoding and TCR clonotype analysis on the 10X Genomics platform, and sequenced by the Stanford Genomics Facility (HighSeq 4000) or Novogene (NovaSeq 6000). Results: We found that circulating CD4+ and CD8+ CAR T cells that express CD57 and T-bet are clonally expanded and display features of effector T cells. In contrast, CD4+ CD57- CAR T cells that express Helios expand polyclonally and display features of T regulatory cells. Conclusions: This study provides insights into cell states of circulating CAR T cells on day 7 that associate with clinical response or toxicity in LBCL patients treated with axi-cel.
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Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that the elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. CAR T cell-produced interferon-gamma (IFN-γ) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell functionality. Mechanistically, iNOS-expressing macrophages upregulated the p53 pathway, mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating the MYC pathway involved in ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in the leukapheresis material of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs) by blocking IFN-g secretion from CAR T cells will improve outcomes for LBCL patients.
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