The Tumor Microenvironment and Inflammation Influence toxicity in patients with Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE153439 | GEO | 2020/07/27
REPOSITORIES: GEO
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Project description:Tumor biopsies were taken within one month prior to CAR T infusion for evaluation of gene expression. Baseline tumor gene expression was compared between patients who went on to have severe (grade 3 or higher) neurotoxicity vs. those with non-severe neurotoxicity (grade 0 - 2).
2020-07-27 | GSE153438 | GEO
Project description:We aimed to identify factors that place patients with Large B Cell Lymphoma at higher risk of developing severe immune mediated toxicities after CAR T infusion. Tumor biopsies were taken within one month prior to CAR T infusion for evaluation of gene expression. In pre-treatment patient tumor biopsies, we found that gene expression of myeloid markers was associated with higher toxicity.
2020-07-27 | GSE153437 | GEO
Project description:PurposeOne of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).Experimental designSerum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.ResultsWe identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.ConclusionsThese results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.
| S-EPMC7501265 | biostudies-literature
Project description:The Tumor Microenvironment and Inflammation Influence toxicity in patients with Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel
| PRJNA642653 | ENA
Project description:The Tumor Microenvironment and Inflammation Influence toxicity in patients with Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel [Nanostring]
| PRJNA642656 | ENA
Project description:The Tumor Microenvironment and Inflammation Influence toxicity in patients with Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel [RNA-Seq]
| PRJNA642648 | ENA
Project description:BackgroundDiffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of lymphoma, and multiple extranodal involvement (ENI) indicates adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on ENI in DLBCL.MethodsThe clinical features of 1960 patients with newly diagnosed DLBCL were analyzed, and DNA and RNA sequencing was performed on 670 and 349 patients, respectively. Oncogenic mutations and tumor microenvironment alterations were compared according to ENI and evaluated in zebrafish patient-derived tumor xenograft models.ResultsMultiple ENI was significantly associated with poor performance status, advanced stage, elevated serum lactate dehydrogenase, low response rate, and inferior prognosis. Lymphoma invasion of the bones, spleen, bone marrow, liver, and central nervous system were independent unfavorable prognostic factors. MYD88 was frequently mutated in patients with multiple ENI, co-occurred with mutations in CD79B, PIM1, TBL1XR1, BTG1, MPEG1, and PRDM1, and correlated with invasion of the bones, kidney/adrenal glands, breasts, testes, skin, and uterus/ovaries. For tumor microenvironment alterations, patients with multiple ENI showed higher regulatory T-cell (Treg)-recruiting activity, but lower extracellular matrix-encoding gene expression, than those without ENI and with single ENI. Elevated Treg-recruiting activity was related to mutations in B2M, SGK1, FOXO1, HIST1H1E, and ARID1A, and correlated with invasion of the bone marrow and thyroid. Additionally, mutations in MYD88, PIM1, TBL1XR1, SGK1, FOXO1, HIST1H1E, and ARID1A were associated with decreased major histocompatibility complex class I expression. Zebrafish models further revealed relationships between MYD88 mutations and invasion of the kidneys and gonads, as well as B2M mutations and invasion of the bone marrow. Increased CXCR4 expression is linked to bone marrow invasion in an organotropic way.ConclusionsOur findings thus contribute to an improved understanding of the biological behavior of multiple ENI and provide a clinical rationale for targeting ENI in DLBCL.
| S-EPMC7685246 | biostudies-literature
Project description:The incidence of diffuse large B-cell lymphoma (DLBCL) increases by age and older DLBCL are commonly related to poor prognosis. However, the clinical and biological features of older DLBCL patients remain to be determined. A total of 2,445 patients with newly diagnosed DLBCL were enrolled for clinical data analysis according to age at diagnosis, with tumor samples of 1,150 patients assessed by DNA sequencing and 385 patients by RNA sequencing. Older DLBCL presented advanced disease stage, elevated serum lactate dehydrogenase, poor performance status, multiple extranodal involvement, high percentage of double expressor subtype, and adverse clinical outcome. According to molecular features, age was positively correlated with the oncogenic mutations of PIM1, MYD88, BTG2, CD79B, TET2, BTG1, CREBBP, TBL1XR1, and with the MYD88-like genetic subtype. These oncogenic mutations were involved in B-cell receptor/NF-κB signaling, B-cell differentiation, and histone acetylation based on biological functions. Older DLBCL also manifested reduction in CD4+ naïve T and CD8+ naïve T cells, and also increased recruitment of exhausted T cells and macrophages, leading to immunosuppressive tumor microenvironment. Our work thus contributes to the understanding of aging-related oncogenic mutations and tumor microenvironment alterations in lymphoma progression, and may provide new insights to mechanism-based targeted therapy in DLBCL.
| S-EPMC8990904 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer that affects ∼22 000 people in the United States yearly. Understanding the complex cellular interactions of the tumor microenvironment is critical to the success and development of DLBCL treatment strategies. In vitro platforms that successfully model the complex tumor microenvironment without introducing the variability of in vivo systems are vital for understanding these interactions. To date, no such in vitro model exists that can accurately recapitulate the interactions that occur between immune cells, cancer cells, and endothelial cells in the tumor microenvironment of DLBCL. To that end, we developed a lymphoma-on-chip model consisting of a hydrogel based tumor model traversed by a vascularized, perfusable, round microchannel that successfully recapitulates key complexities and interactions of the in vivo tumor microenvironment in vitro. We have shown that the perfusion capabilities of this technique allow us to study targeted treatment strategies, as well as to model the diffusion of infused reagents spatiotemporally. Furthermore, this model employs a novel fabrication technique that utilizes common laboratory materials, and allows for the microfabrication of multiplex microvascular environments without the need for advanced microfabrication facilities. Through our facile microfabrication process, we are able to achieve micro vessels within a tumor model that are highly reliable and precise over the length of the vessel. Overall, we have developed a tool that enables researchers from many diverse disciplines to study previously inaccessible aspects of the DLBCL tumor microenvironment, with profound implications for drug delivery and design.
| S-EPMC5285444 | biostudies-literature
Project description:BackgroundAnaplastic diffuse large B-cell lymphoma(A-DLBCL) is a rare morphological subtype characterized by the presence of polygonal, bizarre-shaped tumor cells. Our previous research found that A-DLBCL displays many genetic alterations and biological features that differ greatly from those of ordinary DLBCL. However, the status of tumor immune microenvironment components and checkpoint molecules in A-DLBCL remains unclear.MethodsThirty A-DLBCL patients were enrolled to study tumor immune microenvironment components and checkpoint molecules and their associations with clinicopathological features and prognosis.ResultsPatients with A-DLBCL presented higher expression of PD-L1 (40% vs 10%, P=0.004) than patients with ordinary DLBCL. FISH analysis showed that extra copies of PD-L1 were more frequent in A-DLBCL cases than in ordinary DLBCL cases (23.3% vs 4.0%, P=0.001). The numbers of PD-1+ TILs (tumor infiltrating lymphocytes) and CD8+T cells were significantly lower in A-DLBCL versus ordinary DLBCL. In contrast, the numbers of GATA3+ Th2 cells, FOXP3+ Tregs and CD33+ myeloid-derived suppressor cells (MDSCs) were significantly higher in A-DLBCL than in ordinary DLBCL. The associations between clinicopathological features and tumor immune microenvironment cell frequency were analyzed in A-DLBCL patients. Briefly, the number of PD-1+ TILs was lower and the number of CD33+ MDSCs was higher in patients with mutated TP53 compared to those with wild-type TP53. The number of FOXP3+ Tregs was much lower in patients with a noncomplete response (CR) to chemotherapy than in those with a complete response. The number of CD8+ T cells showed a decreasing trend in patients with high International Prognostic Index (IPI) scores and in those with concurrent MYC and BCL2 and/or BCL6 abnormalities. Univariate survival analysis showed that patients with PD-L1+, mPD-L1+(PD-L1+ nonmalignant stromal cells) or mPD-L1+ status had a significantly poorer overall survival (OS) than those with PD-L1- status. An increase in the number of CD3+ T cells, FOXP3+ Treg cells and T-bet+ Th1 cells was significantly associated with prolonged OS in patients with A-DLBCL.ConclusionOur study suggests that A-DLBCL displays a distinct pattern of tumor immune microenvironment components and checkpoint molecules that distinguish it from ordinary DLBCL. The analysis of tumor immune microenvironment components and checkpoint molecules could help in predicting the prognosis of A-DLBCL patients and determining therapeutic strategies targeting the tumor immune microenvironment.
| S-EPMC8242181 | biostudies-literature