Gene expression changes in mouse kidney cancer cells (RENCA) after anti-PD-L1 resistance
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ABSTRACT:
PROVIDER: PRJNA772175 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16464623_1.fastq.gz | Fastqsanger.gz | |||
| SRR16464623_2.fastq.gz | Fastqsanger.gz | |||
| SRR16464624_1.fastq.gz | Fastqsanger.gz | |||
| SRR16464624_2.fastq.gz | Fastqsanger.gz | |||
| SRR16464625_1.fastq.gz | Fastqsanger.gz |
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Project description:RNA sequencing analysis was used to identify changes in mouse kidney cancer cells (RENCA) following resistance to anti-PD-L1 (PDR).
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Project description:Purpose: To find out the patients who are most sensitive and effective to the anti-PD-L1 and TGF-β bifunctional fusion protein in the treatment of recurrent cervical cancer. Patients and methods: We report two cases of recurrent cervical cancer treated with the anti-PD-L1 and TGF-β bifunctional fusion protein. We described the clinical course, clinical characteristics, and genetic characteristics of the two patients, and analyzed the changes of gene expression in the two patients after treatment. Results: Although PD-L1 expression and HPV status were same in the two patients, the treatment effect of two patients with recurrent cervical cancer was different, according to the evaluation of enhanced computed tomography (CT), one was partial response (PR) and the other was progressive disease (PD), which may indicate that PD-L1 expression and HPV status of patients is not enough to predict the effectiveness of the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Then, we demonstrated that the changes of peripheral blood lymphocytes of two patients during the treatment had different trends. Moreover, number of alterable genes in PR patient is much greater than that in PD patient, indicating PR patient may be more sensible to the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Total 4844 genes changing-fate gene set selected which is believed conducting anti-cancer function during the anti-PD-L1 and TGF-β bifunctional fusion protein treatments. Furthermore, we identified that changing-fate genes were correlated with female reproductive organ cancer, infectious disease, inflammatory disease, immune system, indicating these genes may conducting anti-cancer, anti-inflammation and immune function. Conclusion: Anti-PD-L1 and TGF-β bifunctional fusion protein is feasible for the treatment of recurrent cervical cancer. Multi-center, large-sample prospective clinical studies are still needed to further explore the efficacy of anti-PD-L1 and TGF-β bifunctional fusion protein in recurrent cervical cancer and screen appropriate patients, so as to achieve the maximum survival benefit of patients.
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Project description:Checkpoint inhibitors like anti-PD1/PD-L1 have demonstrated significant therapeutic efficacy in a subset of patients partly through reinvigoration of CD8 T cells. However, their impact on myeloid cells remains largely unknown. Here we report that anti-PD-L1 treatment favorably impacts the phenotype and function of tumor macrophages by polarizing the macrophage compartment towards a more pro-inflammatory phenotype. This phenotype was characterized by a decrease in Arginase-I (ARG1) expression and an increase in iNOS, MHCII, and CD40 expression. Whole-transcriptome profiling further confirmed extensive polarization of both tumor monocytes and macrophages from a suppressive to a pro-inflammatory, immuno-stimulatory phenotype. This polarization was driven mainly through IFNγ and was associated with enhanced T cell activity. Transfer of monocytes into anti-PD-L1-treated tumor-bearing mice led to macrophage differentiation into a more pro-inflammatory phenotype, with an increase in CD8 T cells expressing granzyme B and an increase in the CD8/Treg ratio compared to control-treated mice. While in responsive tumor models anti-PD-L1 treatment remodeled the macrophage compartment with beneficial effects on T cells, both macrophage reprogramming and depletion were needed to maximize anti-PD-L1 responses in a tumor immune contexture with high macrophage burden. Our results demonstrate that anti-PD-L1 treatment can favorably remodel the macrophage compartment in responsive tumor models towards a more pro-inflammatory phenotype, mainly through increased IFNγ levels. They also suggest that directly targeting these cells with reprogramming and depleting agents may further augment the breadth and depth of response to anti-PD-L1 treatment in less responsive or more macrophage-dense tumor microenvironments. The "SAMPLE_ID" sample characteristic is a sample identifier internal to Genentech. The ID of this project in Genentech's ExpressionPlot database is NGS1772.
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Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
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