Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Alvarez‐Breckenridge, Christopher; Markson, Samuel C.; Stocking, Jackson H.; Nayyar, Naema; Lastrapes, Matt; Strickland, Matthew R.; Kim, Albert E.; Sauvage, Magali de; Dahal, Ashish; Larson, Juliana M.; Mora, Joana L.; Navia, Andrew W.; Klein, Robert H.; Kuter, Benjamin M.; Gill, Corey M.; Bertalan, Mia; Shaw, Brian; Kaplan, Alexander; Subramanian, Megha; Jain, Aarushi; Kumar, Swaminathan; Danish, Husain; White, Michael; Shahid, Osmaan; Pauken, Kristen E.; Miller, Brian C.; Frederick, Dennie T.; Hebert, Christine; Shaw, McKenzie; Martinez‐Lage, Maria; Frosch, Matthew P.; Wang, Nancy; Gerstner, Elizabeth R.; Nahed, Brian V.; Curry, William T.; Carter, Bob S.; Cahill, Daniel P.; Boland, Genevieve M.; Izar, Benjamin; Davies, Michael A.; Sharpe, Arlene H.; Suvà, Mario L.; Sullivan, Ryan J.; Brastianos, Priscilla K.; Carter, Scott L.

doi:10.1158/2326-6066.cir-21-0870

“…(A) UMAP dimensionality reduction of cells, annotated as all cells clustering (right panel) and FasL expression level in a specific cell population (left panel). Datasets were extracted from the Single Cell PORTAL (Broad Institute) . (B) UMAP dimensionality reduction of cells, annotated as T cell subpopulations (right panel) and FasL expression level in specific T cell subpopulations (left panel).…”

Section: Resultsmentioning

confidence: 99%

“…Human Patient Tumor Sample Single-Cell RNA Sequencing (scRNA-Seq) Datasets. Human melanoma patient scRNA-Seq datasets were collected from the Single Cell PORTAL (Broad Institute) 76 and GEO database (GSE115978). 77 Human normal tissue single-cell datasets were collected from the data deposited in the Single Cell PORTAL.…”

Section: Methodsmentioning

confidence: 99%

Lipid Nanoparticle Delivery of Fas Plasmid Restores Fas Expression to Suppress Melanoma Growth In Vivo

Subeh

¹

,

Poschel

²

,

Redd

³

et al. 2022

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Fas ligand (FasL), expressed on the surface of activated cytotoxic T lymphocytes (CTLs), is the physiological ligand for the cell surface death receptor, Fas. The Fas-FasL engagement initiates diverse signaling pathways, including the extrinsic cell death signaling pathway, which is one of the effector mechanisms that CTLs use to kill tumor cells. Emerging clinical and experimental data indicate that Fas is essential for the efficacy of CAR-T cell immunotherapy. Furthermore, loss of Fas expression is a hallmark of human melanoma. We hypothesize that restoring Fas expression in tumor cells reverses human melanoma resistance to T cell cytotoxicity. DNA hypermethylation, at the FAS promoter, down-regulates FAS expression and confers melanoma cell resistance to FasL-induced cell death. Forced expression of Fas in tumor cells overcomes melanoma resistance to FasL-induced cell death in vitro. Lipid nanoparticle-encapsulated mouse Fas-encoding plasmid therapy eliminates Fas + tumor cells and suppresses established melanoma growth in immune-competent syngeneic mice. Similarly, lipid nanoparticle-encapsulated human FAS-encoding plasmid (hCOFAS01) therapy significantly increases Fas protein levels on tumor cells of human melanoma patient-derived xenograft (PDX) and suppresses the established human melanoma PDX growth in humanized NSG mice. In human melanoma patients, FasL is expressed in activated and exhausted T cells, Fas mRNA level positively correlates with melanoma patient survival, and nivolumab immunotherapy increases FAS expression in tumor cells. Our data demonstrate that hCOFAS01 is an effective immunotherapeutic agent for human melanoma therapy with dual efficacy in increasing tumor cell FAS expression and in enhancing CTL tumor infiltration.

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“…EMT is a complex biological process, and the regulatory network consists of multiple miRNAs and target genes, and its role in predicting GC patients has received increasing attention [15]. Many studies have reported that the EMT process is related to the lymph node metastasis process of malignant tumors [16].…”

Section: Discussionmentioning

confidence: 99%

Construction of epithelial-mesenchymal transition related miRNAs signatures as prognostic biomarkers in gastric cancer patients

Xiao

¹

,

Zhang

²

,

Liu

³

et al. 2022

Preprint

0

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Aim: To identify the potential post-healing EMT related miRNAs associated with lymph node metastatic gastric cancer (LNMGC). Methods: Both RNA expression and clinical medical data were obtained from the TCGA dataset. We performed differential expression and normalization analysis of miRNAs. Cox linear regression model confirmed the differentially expressed miRNAs (DEmiRNAs) and clinical medical parameters related to overall survival (OS). The role of target genes of DEmiRNAs was determined according to the role enrichment analysis. Results: We obtained a total of 7531 DEmRNAs and 267 DEmRNAs, of which 185 DEmRNAs were down-regulated and 82 DEmRNAs were up-regulated. We randomly divided the LMNGC cases (n=291) into a training group (n=207) and a test group (n=84). The results showed that a total of 103, 11, 13 and 83 overlapping genes were associated with hsa-mir-141-3p, hsa-mir-4664-3p, hsa-mir-125b-5p and hsa-mir-7-5p, respectively. Kaplan-Meier determined that these four miRNAs can effectively distinguish high-risk and low-risk groups, and have a good indicator role (all p<0.05). Multivariate cox regression analysis also showed that EMT-related miRNA predictive model and lymph node metastasis were both prognostic risk factors (all p<0.05). The ROC curve showed that this feature had high accuracy (AUC>0.7, p<0.05). In addition, KEGG analysis showed that EMT-related pathways were mainly enriched in HIF-1 signaling pathway and focal adhesion. Conclusions: Our study demonstrated that EMT-related miRNAs could serve as independent prognostic markers in pN 1-3 GC patients.

show abstract

“…EMT is a complex biological process, and the regulatory network consists of multiple miRNAs and target genes, and its role in predicting GC patients has received increasing attention [15]. Many studies have reported that the EMT process is related to the lymph node metastasis process of malignant tumors [16].…”

Section: Discussionmentioning

confidence: 99%

Construction of epithelial-mesenchymal transition related miRNAs signatures as prognostic biomarkers in gastric cancer patients

Xiao

¹

,

Zhang

²

,

Liu

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Aim: To identify the potential post-healing EMT related miRNAs associated with lymph node metastatic gastric cancer (LNMGC). Methods: Both RNA expression and clinical medical data were obtained from the TCGA dataset. We performed differential expression and normalization analysis of miRNAs. Cox linear regression model confirmed the differentially expressed miRNAs (DEmiRNAs) and clinical medical parameters related to overall survival (OS). The role of target genes of DEmiRNAs was determined according to the role enrichment analysis. Results: We obtained a total of 7531 DEmRNAs and 267 DEmRNAs, of which 185 DEmRNAs were down-regulated and 82 DEmRNAs were up-regulated. We randomly divided the LMNGC cases (n=291) into a training group (n=207) and a test group (n=84). The results showed that a total of 103, 11, 13 and 83 overlapping genes were associated with hsa-mir-141-3p, hsa-mir-4664-3p, hsa-mir-125b-5p and hsa-mir-7-5p, respectively. Kaplan-Meier determined that these four miRNAs can effectively distinguish high-risk and low-risk groups, and have a good indicator role (all p<0.05). Multivariate cox regression analysis also showed that EMT-related miRNA predictive model and lymph node metastasis were both prognostic risk factors (all p<0.05). The ROC curve showed that this feature had high accuracy (AUC>0.7, p<0.05). In addition, KEGG analysis showed that EMT-related pathways were mainly enriched in HIF-1 signaling pathway and focal adhesion. Conclusions: Our study demonstrated that EMT-related miRNAs could serve as independent prognostic markers in pN1-3 GC patients.

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Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Cited by 29 publications

References 68 publications

Lipid Nanoparticle Delivery of Fas Plasmid Restores Fas Expression to Suppress Melanoma Growth In Vivo

Lipid Nanoparticle Delivery of Fas Plasmid Restores Fas Expression to Suppress Melanoma Growth In Vivo

Construction of epithelial-mesenchymal transition related miRNAs signatures as prognostic biomarkers in gastric cancer patients

Construction of epithelial-mesenchymal transition related miRNAs signatures as prognostic biomarkers in gastric cancer patients

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