Mice melanoma treated by anti-PD1 and intra-tumor microbiome
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205896 | GEO | 2024/06/01
REPOSITORIES: GEO
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Project description:Mice melanoma treated by anti-PD1 and intra-tumor microbiome
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Project description:There is a growing appreciation of the role of the microbiome in cancer, and evidence in pre-clinical models that the gut microbiome may modulate responses to immune checkpoint blockade though this has not been well-characterized in patients. We analyzed the oral (n=86)and gut (n=43) 16S microbiome in melanoma patients on PD-1 blockade. Significant differences were noted in the diversity and composition of the gut microbiome between responders and non-responders in patients with a fecal microbiome sample, with significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria) in R. Metagenomic studies (n=25) revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling demonstrated enhanced systemic and anti-tumor immunity in patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplant from responding patients. Together, these data have important implications for treatment with immune checkpoint blockade in cancer.
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Project description:Nuclear receptors (NRs) are implicated in the regulation of tumors and immune cells. We identify a tumor-intrinsic function of the orphan NR, NR2F6, regulating anti-tumor immunity. NR2F6 was selected from 48 candidate NRs, based on an expression pattern in melanoma patient specimens (i.e., IFN signature) associated with positive responses to immunotherapy and favorable patient outcomes. Correspondingly, genetic ablation of NR2F6 in a mouse melanoma model conferred a more effective response to PD-1 therapy. NR2F6 loss in B16F10 and YUMM1.7 melanoma cells attenuated tumor development in immune-competent but not -incompetent mice via the increased abundance of effector and progenitor-exhausted CD8+ T cells. Inhibition of NACC1 and FKBP10, identified as NR2F6 effectors, phenocopied NR2F6 loss. Remarkably, inoculation of NR2F6 KO mice with NR2F6 KD melanoma cells further decreased tumor growth compared with NR2F6 WT mice. Tumor-intrinsic NR2F6 function complements its tumor-extrinsic role and justifies the development of novel anti-cancer therapies.
2023-09-11 | GSE228162 | GEO
Project description:NK cells, as a type of key immune cell, play essential roles in tumor cell immune escape and immunotherapy. Accumulating evidence has demonstrated that the gut microbiota community affects the efficacy of anti-PD1 immunotherapy and that remodeling the gut microbiota structure is a promising strategy to enhance anti-PD1 immunotherapy responsiveness in advanced melanoma patients; however, the details of the mechanism remain elusive. In this study, we found that Eubacterium rectale (E. rectale) was significantly enriched in melanoma patients who responded to anti-PD1 immunotherapy and a high E. rectale abundance was related to longer survival in melanoma patients. Furthermore, administration of E. rectale remarkably improved the efficacy of anti-PD1 therapy and benefited the overall survival of tumor-bearing mice; moreover, application of E. rectale significantly recruited NK cells into the tumor microenvironment. Interestingly, conditioned medium isolated from an E. rectale culture system dramatically enhanced NK-cell function. Through GC-MS/ UHPLC-MS/MS-based metabolomic analysis, L-serine production was found to be significantly decreased in the E. rectale group; moreover, administration of an L-serine synthesis inhibitor dramatically increased NK-cell activation, which led to enhanced anti-PD1 immunotherapy effects. Mechanistically, supplementation with L-serine or application of the L-serine synthesis inhibitor affected NK-cell activation through Fos/Fosl. In summary, our findings reveal the role of bacteria-modulated serine metabolic signaling in NK-cell activation and provide a novel therapeutic strategy to improve the efficacy of anti-PD1 immunotherapy in melanoma.
2023-04-14 | GSE225920 | GEO
Project description:Recent success in cancer immunotherapy has come from the blockade of inhibitory receptors on T cells, such as programmed cell death-1, which can induce a state of T cell exhaustion upon constant antigen stimulation. Understanding miRNA regulation of PD1 can be useful to discover miRNAs for use in therapy or as prognostic markers in various diseases including cancer, autoimmunity and transplantation. We used microarrays to discover global miRNA expression changes upon PD1 upregulation and identified miRNAs that are both up- and down-regulated. B16F10 cells were injected subcutaneously into C57BL/6 mice and 16 days later CD4+PD1+ and CD4+PD1- were sorted from the lymph nodes and spleen for RNA extraction and hybridization on Affymetrix miRNA array.
2015-08-01 | E-GEOD-65208 | biostudies-arrayexpress
Project description:We evaluated blood samples from 6 patients with metastatic melanoma treated with anti-LAG3+anti-PD1 (160+480 mg) in a phase I trial (NCT01968109) using single-cell RNA and T cell receptor (TCR) sequencing (scRNA+TCRαβ-seq, 10X 5') combined with other multiomics profiling (flow, cytokine, TCRb-seq) from a larger cohort of 40 patients. This data set include three time points, including baseline, 1 month, and 3 month. The sorting is CD45+.
2023-02-03 | E-MTAB-12733 | biostudies-arrayexpress
Project description:Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma; However, predicting which patients will respond to immunotherapy is still unknown. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE, a negative regulator of NF-kB, were found exclusively in the responders. NKBIE-related genes within the responder group were also enriched compared to the non-responders. Patients that harbored NFKBIE-related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subsection of tumor samples identified differential expression of the TNFA signaling via NFKB pathway, which includes CD83. By overexpressing NFKBIEG34E we were able to demonstrate this mutation is related to increased NF-kB activity, including increased CD83 protein expression when compared with the wildtype. These results suggest that increased NF-kB signaling as a consequence of an NFKBIE mutation may contribute to a favorable anti-PD1 treatment response, including a possible novel role of CD83 in solid tumors.
2020-08-07 | GSE145996 | GEO
Project description:The effect of TIM-3 stimulation was studied on B16F10 mouse melanoma cells, in vitro. Experiment Overall Design: Cy3: B16F10 mouse melanoma cells, treated by unspecific goat IgG (control) for 2 hours. Experiment Overall Design: Cy5: B16F10 mouse melanoma cells, in vitro, treated by an agonist goat polyclonal anti-mouse TIM3 antibody (RnD Systems) for 2 hours. Experiment Overall Design: Four biological replicates were used (in this study, biological replicate means different passage numbers of the same cell line). In each case, the treated sample (Cy5) was compared to its control one (Cy3) in Agilent dual-color microarray experiments.
2009-10-15 | E-GEOD-14418 | biostudies-arrayexpress
Project description:Patients with advanced melanoma have shown an improved outlook after receiving anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapy efficacy remains a major challenge. Here, our findings show significantly higher abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanomas via STAT1/3. We also found that supplementation with α-KG significantly increased methylcytosine dioxygenase TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 had been recognized and stabilized in PD-L1 promoter to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that the TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, we provide a novel insight into α-KG's function in melanoma anti-PD1 treatment and supplement of α-KG is a novel promising strategy to improve the efficacy of anti-PD1 therapy.
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Project description:BMP2 treatment significantly reduces growth of B16F10 melanoma spheroids. This experiment analyses the transcriptome changes in B16F10 cells treated with or without BMP2.
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