Whole genome sequencing identified biomarker of response to PD1 blockade in Natural-killer/T-cell lymphoma
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PROVIDER: EGAS00001002420 | EGA |
REPOSITORIES: EGA
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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:Immuno-LC-PRM assay was developed to simultaneously quantify the expression levels of six immune markers (CD8A, CD4, LAG3, PD1, PD-L1 and PD-L2) using as little as 1-2 mg of fresh frozen tissue.
2018-10-04 | PXD011152 | Pride
Project description:Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we performed bulk-RNA seq on resected tumor tissue in an additional 25 patients with surgically-accessible recurrent glioblastoma. Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.
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Project description:Introduction: Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)–PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes. Methods: We applied a second-generation in situ proximity ligation assay to detect PD1–PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from 140 patients with advanced NSCLC with and without ICI treatment. RNA sequencing analysis was used to identify potential resistance mechanisms. Results: In the early-stage NSCLC, only approximately half of the cases with detectable PD-L1 and PD1 expression exhibited PD1–PD-L1 interactions, with significantly lower levels in EGFR-mutated tumors. Interaction levels varied across cancer types, aligning with reported ICI response rates. In ICI-treated patients with NSCLC, higher PD1–PD-L1 interactions were linked to complete responses and longer survival, outperforming standard PD-L1 expression assays. Patients who did not respond to ICIs despite high PD1–PD-L1 interactions exhibited additional expression of stromal immune mediators (EOMES, HAVCR1/TIM-1, JAML, FCRL1). Conclusion: Our study proposes a diagnostic shift from static biomarker quantification to assessing active immune pathways, providing more precise ICI treatment. This functional concept applies to tiny lung biopsies and can be extended to further immune checkpoints. Accordingly, our results indicate concerted ICI resistance mechanisms, highlighting the need for combination diagnostics and therapies.
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Project description:Functional impairment of the immune response to chronic viral infections and malignancies is characterised by exhausted T cells, which do not respond to antigen. The cell surface receptor PD1 has been implicated in the maintenance of T cell exhaustion and is an attractive target for immunomodulatory approaches to the treatment of such conditions. However, the mechanisms by which PD1 signalling causes exhaustion and the exact response of T cells to PD1 activation are not clear although it has been suggested that PD1 up regulates a number of anti-proliferative factors. Here we perform cytokine and transcriptional profiling of uninfected primary human T cells to characterise these events. We find that PD1 completely prevents cytokine and transcrip- tional changes induced by CD3/28 stimulation. We do not see any factors specifically induced by PD1, including BATF or IL10 which have previously been linked to PD1 activity. Together with the work of others this confirms that PD1 is the sole effector of T cell exhaustion and that infection is responsible for BATF and IL10 up regulation. As a consequence future therapeutic strategies will be confined to the inhibition of PD1 and not a downstream effector.
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Project description:Immunotherapies have shown remarkable, albeit tumor-selective therapeutic benefits in the clinic. Here we evaluated the effects of the immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer resistant to checkpoint and other immunotherapies. PD1-IL2v is a bi-specific molecule based on a bivalent PD-1 antibody, serving as a targeting moiety, fused to an immuno-stimulatory IL-2 variant (IL2v) to precisely deliver IL2v to PD-1+ T-cells in the tumor microenvironment. PD1-IL2v elicited dramatic infiltration by CD8 T cells, notably stem-like and effector memory T cells, resulting in tumor regression and enhanced survival in mice. Furthermore, combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and tumor endothelial cells , and by enhancing TCR immune repertoire diversity. The data motivate consideration of clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, especially in immunotherapy-resistant tumors infiltrated with PD-1+ T stem-like CD8 T cells.
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Project description:Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RASwt) CRC. In this post hoc secondary analysis, we show that patients with TP53 mutant (p53mt) tumors had significantly higher progression-free survival (PFS) and decrease in tumor burden compared to patients with TP53 wild-type (p53wt) tumors. The gene set enrichment analysis showed uniform upregulation in several metabolic gene sets and most immune gene sets including NK-mediated immunity and IL-12 pathway while the IL6 pathway was downregulated. While there were no overlapping transcriptional alterations between the p53mt and p53wt groups with treatment that remain constant despite the therapeutic intervention, we did identify functional overlap with treatment in both groups in proliferative, immune, and metabolic pathways. In the pre-treatment tumor samples, the number of PD-L1+ tumor cells was significantly higher in p53mt tumors while the number of exhausted-1 immune cells (defined as OX40-/AE1_AE3-/PD-L1- cells, positive for 1/3 exhaustion markers, LAG3 or CTLA4 or TIM3) was significantly higher in p53wt tumors. In conclusion, TP53 status was prognostic of improved disease control with cetuximab plus pembrolizumab in RASwt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RASwt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).
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Project description:Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RASwt) CRC. In this post hoc secondary analysis, we show that patients with TP53 mutant (p53mt) tumors had significantly higher progression-free survival (PFS) and decrease in tumor burden compared to patients with TP53 wild-type (p53wt) tumors. The gene set enrichment analysis showed uniform upregulation in several metabolic gene sets and most immune gene sets including NK-mediated immunity and IL-12 pathway while the IL6 pathway was downregulated. While there were no overlapping transcriptional alterations between the p53mt and p53wt groups with treatment that remain constant despite the therapeutic intervention, we did identify functional overlap with treatment in both groups in proliferative, immune, and metabolic pathways. In the pre-treatment tumor samples, the number of PD-L1+ tumor cells was significantly higher in p53mt tumors while the number of exhausted-1 immune cells (defined as OX40-/AE1_AE3-/PD-L1- cells, positive for 1/3 exhaustion markers, LAG3 or CTLA4 or TIM3) was significantly higher in p53wt tumors. In conclusion, TP53 status was prognostic of improved disease control with cetuximab plus pembrolizumab in RASwt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RASwt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).
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