Pathway Signatures Derived from On-treatment Tumor Specimens Predict Response to Anti-PD1 Blockade in Metastatic Melanoma
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ABSTRACT:
PROVIDER: PRJNA706446 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13853353_1.fastq.gz | Fastqsanger.gz | |||
| SRR13853353_2.fastq.gz | Fastqsanger.gz | |||
| SRR13853354_1.fastq.gz | Fastqsanger.gz | |||
| SRR13853354_2.fastq.gz | Fastqsanger.gz | |||
| SRR13853355_1.fastq.gz | Fastqsanger.gz |
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Project description:Both genomic and transcriptomic signatures have been developed to predict responses of metastatic melanoma to immune checkpoint blockade (ICB) therapies; however, most of these signatures are derived from pre-treatment biopsy samples. Here, we build pathway-based super signatures in pre-treatment (PASS-PRE) and on-treatment (PASS-ON) tumor specimens based on transcriptomic data and clinical information from a large dataset of metastatic melanoma treated with anti-PD1-based therapies as the training set. Both PASS-PRE and PASS-ON signatures are validated in three independent datasets of metastatic melanoma as the validation set, achieving area under the curve (AUC) values of 0.45-0.69 and 0.85-0.89, respectively. We also combine all test samples and obtain AUCs of 0.65 and 0.88 for PASS-PRE and PASS-ON signatures, respectively. When compared with existing signatures, the PASS-ON signature demonstrates more robust and superior predictive performance across all four datasets. Overall, we provide a framework for building pathway-based signatures that is highly and accurately predictive of response to anti-PD1 therapies based on on-treatment tumor specimens. This work would provide a rationale for applying pathway-based signatures derived from on-treatment tumor samples to predict patients' therapeutic response to ICB therapies.
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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.
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Project description:Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the PD1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-CTLA-4 when combined with anti-PD1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient since CD8+ T cells from Cxcr3+/+ but not Cxcr3–/– mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 “priming” with chemotherapy followed by anti-PD1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.
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