Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti-PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1+CD8+ T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1+CD8+ T cells. Taken together, we found a subset of PD-1 therapy-responsive CD8+ T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1+CD8+ T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.
Less than 15% of more than 400 SIDS cases had a "potentially informative" variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families.
Background Autologous transplantation of mesenchymal stem cells (MSCs) may be a viable option for the treatment of several diseases. Evidence indicates that MSCs release extracellular vesicles (EVs) that shuttle miRNAs to damaged parenchymal cells, activating an endogenous repair program. However, whether comorbidities, such as metabolic syndrome (MetS) interfere with the packaging of cargo of MSC-derived EVs has never been explored. We hypothesized that MetS modulates the miRNA content packed within MSC-derived EVs. Methods MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet (n=7 each). Next-generation miRNA sequencing (miRNA-seq) was performed to identify miRNAs enriched in MSC-derived EVs, and their predicted target genes. Functional pathway analysis of the top 50 target genes of the top 4 miRNAs enriched in each group was performed using FunRich. Results Fourteen and 8 miRNAs were enriched in Lean- and MetS- EVs, respectively. Target genes of miRNAs enriched in MetS-EVs were implicated in the development of MetS and its complications, including diabetes-related pathways, validated transcriptional targets of AP1 family members Fra1 and Fra2, Class A/1 (Rhodopsin-like receptors), and Peptide ligand-binding receptors. Contrarily, miRNAs enriched in Lean EVs target primarily EphrinA-EPHA and the Rho family of GTPases. Conclusions MetS alters the miRNA content of EVs derived from porcine adipose tissue MSCs. These alterations could impair the efficacy of autologous MSCs and limit its therapeutic use in subjects with MetS. Our findings may assist in developing adequate regenerative strategies to preserve the reparative potency of MSCs in individuals with MetS.
INTRODUCTION We hypothesized that common Alzheimer’s disease (AD)-associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression. METHODS Expression microarrays on temporal cortex and cerebellum from ~400 neuropathologically diagnosed subjects, and two independent RNAseq replication cohorts were used for expression quantitative trait locus (eQTL) analysis. RESULTS A variant within a DNase hypersensitive site 5′ of TREM2, rs9357347-C, associates with reduced AD-risk and increased TREML1 and TREM2 levels (uncorrected-p=6.3×10-3 and 4.6×10-2, respectively). Meta-analysis on eQTL results from three independent datasets (n=1,006) confirmed these associations (uncorrected-p=3.4×10−2 and 3.5×10−3, Bonferroni-corrected p=6.7×10−2 and 7.1×10−3, respectively). DISCUSSION Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer’s Project (IGAP) GWAS meta-analysis, and suggest concomitant increase of TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.
As patient derived xenograft (PDX) models are increasingly used for preclinical drug development, strategies to account for the nonhuman component of PDX RNA expression data are critical to its interpretation. A bioinformatics pipeline to separate donor tumor and mouse stroma transcriptome profiles was devised and tested. To examine the molecular fidelity of PDX versus donor tumors, we compared mRNA differences between paired PDX-donor tumors from nine ovarian cancer patients. 1,935 differentially expressed genes were identified between PDX and donor tumors. Over 90% (n = 1767) of these genes were down-regulated in PDX models and enriched in stroma-specific functions. Several protein kinases were also differentially expressed in PDX tumors, e.g. PDGFRA, PDGFRB and CSF1R. Upon in silico removal of these PDX-donor tumor differentially expressed genes, a stronger transcriptional resemblance between PDX-donor tumor pairs was seen (average correlation coefficient increases from 0.91 to 0.95). We devised and validated an effective bioinformatics strategy to separate mouse stroma expression from human tumor expression for PDX RNAseq. In addition, we showed most of the PDX-donor differentially expressed genes were implicated in stromal components. The molecular similarities and differences between PDX and donor tumors have implications in future therapeutic trial designs and treatment response evaluations using PDX models.
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