Methylation cytometric pretreatment blood immune profiles with tumor mutation burden as prognostic indicators for survival outcomes in head and neck cancer patients on anti-PD-1 therapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE277573 | GEO | 2024/11/15
REPOSITORIES: GEO
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Project description:This ordinary differential equation model simulating the mechanisms that govern cancer-immune dynamics and their role in tumor responses to immunotherapy is described by the publication:
Creemers JHA, Lesterhuis WJ, Mehra N, et al.
"A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery."
Journal for ImmunoTherapy of Cancer 2021;9:e002032.
doi:10.1136/jitc-2020-002032
Comment:
Simulation parameters in supplementary table 1 mismatch with figure 1 in manuscript. Therefore, to clarify, the following parameter values were used:
Reproduction of Fig. 1(C), xi = 0.0005
Reproduction of Fig. 1(D), xi = 0.00025
Abstract:
Background: Predicting treatment response or survival of cancer patients remains challenging in immuno-oncology. Efforts to overcome these challenges focus, among others, on the discovery of new biomarkers. Despite advances in cellular and molecular approaches, only a limited number of candidate biomarkers eventually enter clinical practice.
Methods: A computational modeling approach based on ordinary differential equations was used to simulate the fundamental mechanisms that dictate tumor-immune dynamics and to investigate its implications on responses to immune checkpoint inhibition (ICI) and patient survival. Using in silico biomarker discovery trials, we revealed fundamental principles that explain the diverging success rates of biomarker discovery programs.
Results: Our model shows that a tipping point—a sharp state transition between immune control and immune evasion—induces a strongly non-linear relationship between patient survival and both immunological and tumor-related parameters. In patients close to the tipping point, ICI therapy may lead to long-lasting survival benefits, whereas patients far from the tipping point may fail to benefit from these potent treatments.
Conclusion: These findings have two important implications for clinical oncology. First, the apparent conundrum that ICI induces substantial benefits in some patients yet completely fails in others could be, to a large extent, explained by the presence of a tipping point. Second, predictive biomarkers for immunotherapy should ideally combine both immunological and tumor-related markers, as a patient’s distance from the tipping point can typically not be reliably determined from solely one of these. The notion of a tipping point in cancer-immune dynamics helps to devise more accurate strategies to select appropriate treatments for patients with cancer.
2024-09-02 | BIOMD0000001022 | BioModels
Project description:A significant percentage of HIV-infected individuals experience a sharp decline in CD4+ T cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) versus chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy. mRNA and miRNA expression profiles in the peripheral blood mononuclear cells (PBMCs) of RPs and CPs were investigated at 111±22 days (Mean±SD) of HIV infection. The association of mRNA and miRNA expression with disease progression was examined by receiver operating characteristic analysis and Kaplan-Meier survival analysis. Pathway enrichment analysis showed that genes with deregulated expression in RPs are primarily involved in apoptosis pathways. Furthermore, we found that 5 miRNAs (miR-31, -200c, -526a, -99a and -503) in RPs were significantly decreased compared to those in CPs (P<0.05). The decreased expression of these miRNAs was associated with rapid disease progression of HIV infection with a 94% predictive value as measured by the area under the curve. The upregulated predicted targets from the 5 signature miRNAs and all upregulated genes identified from mRNA microarray converged to the apoptosis pathway. Moreover, overexpression of miR-31 in primary human T cells promoted their survival. Our results have identified a distinct transcriptomic signature in PBMCs of RPs and provided novel insights to the pathogenesis of HIV infection. The initial 347 miRNA array was performed in 11 RPs, 6 CPs and 4 corresponding matched normal controls (training group); and only the miRNAs differentially expressed between RPs and CPs (P<0.05) in training group were detected in a subsequent validation group (19 RPs versus 10 CPs). miRNAs differentially expressed in 17 early HIV infected patients (including 11 RPs and 6 CPs) and 4 healthy controls in training cohort were firstly identified. Then, miRNAs differed RPs from CPs were compared in both training and validation cohort.
2013-05-01 | E-GEOD-44332 | biostudies-arrayexpress
Project description:Background Skeletal morbidity in cancer patients has a major impact on quality of life and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune-checkpoint inhibitors (ICI) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICI on bone turnover by longitudinal assessment of bone turnover markers (BTM) in cancer patients and by validation in a novel bioengineered 3D model of bone remodeling. Methods Serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-propeptide, PINP; and osteocalcin, OCN) were measured before each ICI application (PD1 inhibitors, PD1i or PD-L1 inhibitors, PD1i) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation upon treatment with ICI. In addition, their effect on bone remodeling was assessed by immunohistochemistry, immunofluorescence and proteomics analysis in a dynamic 3D model of the bone multicellular unit (BMU). Results The longitudinal assessment of BTM revealed a significant decrease in CTX levels after 3 weeks, followed by a return to baseline levels within 3 months. In contrast, serum levels of PINP and OCN gradually increased from baseline to the last postbaseline assessment. In vitro, ICI impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling, but not JNK, ERK and AKT; while lacking any direct effect on osteogenesis. However, using our novel bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity upon ICI treatment by demonstrating impaired OC maturation along with increased OB differentiation. Conclusion Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with the OB/OC coupling of bone turnover and may potentially exert a protective effect on bone by impairing the differentiation OCs and indirectly promoting osteogenesis.
2024-05-21 | PXD047604 | Pride
Project description:Immune checkpoint inhibitors (ICIs) represent promising treatment for hepatocellular carcinoma (HCC) due to abundant lymphocyte infiltration. However, some HCC patients respond poorly to ICI therapy due to the presence of various immunosuppressive factors in tumor microenvironment. Our research revealed that macrophage-coated tumor clusters (MCTCs) signified a unique spatial structural organization in HCC, correlating with diminished recurrence-free survival (RFS) and overall survival (OS) in a total of 572 HCC cases from 3 internal cohorts and 2 external validation cohort independently. Mechanistically, Tumor-derived M2BP induced MCTCs formation, and entrapped immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cells exclusion and local immune deprivation. Combined treatment of anti-PD-1 antibody and Mac-2 antagonist GB1107 before MCTC formation could significantly attenuated HCC growth and inhibited HCC metastasis in vivo by recovering intratumoral infiltration of cytotoxic T cells, offering a potential strategy to enhance ICI efficacy in HCC.
2024-06-12 | GSE248907 | GEO
Project description:We designed a Phase II clinical trial testing the combination of guadecitabine (DNMTi) and atezolizumab (anti-PD-L1) with the goal to re-stimulate the immune mediated anticancer effects of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma patients who were resistant to prior ICI treatment. No RECIST criteria responses were observed, however, patients could be separated into those with either progressive or stable disease outcomes. Analysis of the tumors did not show substantial DNA hypomethylation in the tumor or the upregulation of viral mimicry after two cycles of combination treatment. We did, however, observe that the therapy associated with immune activation of circulating immune cells and abundance of tumor-infiltrating CD8 T cells within the tumor, which were correlated with a longer survival outcome. Our results suggest that further studies to target the reprogramming of T cells with alternate methodologies may be of benefit in this disease setting.
2023-03-01 | GSE222933 | GEO
Project description:We designed a Phase II clinical trial testing the combination of guadecitabine (DNMTi) and atezolizumab (anti-PD-L1) with the goal to re-stimulate the immune mediated anticancer effects of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma patients who were resistant to prior ICI treatment. No RECIST criteria responses were observed, however, patients could be separated into those with either progressive or stable disease outcomes. Analysis of the tumors did not show substantial DNA hypomethylation in the tumor or the upregulation of viral mimicry after two cycles of combination treatment. We did, however, observe that the therapy associated with immune activation of circulating immune cells and abundance of tumor-infiltrating CD8 T cells within the tumor, which were correlated with a longer survival outcome. Our results suggest that further studies to target the reprogramming of T cells with alternate methodologies may be of benefit in this disease setting.
2023-03-01 | GSE222932 | GEO
Project description:A significant percentage of HIV-infected individuals experience a sharp decline in CD4+ T cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) versus chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy. mRNA and miRNA expression profiles in the peripheral blood mononuclear cells (PBMCs) of RPs and CPs were investigated at 111±22 days (Mean±SD) of HIV infection. The association of mRNA and miRNA expression with disease progression was examined by receiver operating characteristic analysis and Kaplan-Meier survival analysis. Pathway enrichment analysis showed that genes with deregulated expression in RPs are primarily involved in apoptosis pathways. Furthermore, we found that 5 miRNAs (miR-31, -200c, -526a, -99a and -503) in RPs were significantly decreased compared to those in CPs (P<0.05). The decreased expression of these miRNAs was associated with rapid disease progression of HIV infection with a 94% predictive value as measured by the area under the curve. The upregulated predicted targets from the 5 signature miRNAs and all upregulated genes identified from mRNA microarray converged to the apoptosis pathway. Moreover, overexpression of miR-31 in primary human T cells promoted their survival. Our results have identified a distinct transcriptomic signature in PBMCs of RPs and provided novel insights to the pathogenesis of HIV infection. A cohort of primary HIV infected individuals with different disease outcome were enrolled in this study. We included 6 individuals with rapid disease progression (RP), seven with chronic disease progression (CP). The HIV infected individuals were never on therapy before the time of sample taken.
2013-05-01 | E-GEOD-44216 | biostudies-arrayexpress
Project description:Due to scarcity of effective therapeutic targets, metastatic TNBC (mTNBC) has shorter survival times compared to other advanced breast cancer subtypes. Although chemo-immunotherapy with immune checkpoint inhibitors (ICIs) in PD-L1+ mTNBC has shown promise, survival benefit remains modest. Therefore, it is crucial to gain improved insight into the mechanisms underlying response and resistance to checkpoint inhibition in mTNBC. We employed single cell-RNA-sequencing, single cell secretomics, and flow cytometry to identify transcriptomic and proteomic peripheral immune cell signatures associated with response and non-response to anti-PD-1/PD-L1 therapy and chemotherapy in mTNBC. Transcriptomic analysis revealed divergent transcriptional programming of CD33+ myeloid cells between responders and non-responders, even in pretreatment PBMC samples. This divergence, in responders, was characterized by an immune-promoting CD33+ cell phenotype involving IL-1b signaling versus, in non-responders, an immunosuppressive phenotype marked by IL-1b inhibition. These baseline differences expanded during the course of treatment. Differences in CD33+ cell phenotype resulted in functional differences in lymphocyte activities between responders and non-responders. To confirm this causal role of myeloid cells, we depleted CD33+ cells in pre-treatment samples from non-responders, which led to a rescue of T cell effector function. Our findings highlight CD33+ cell phenotype as a key determinant of response to chemo-immunotherapy, which can be assessed from peripheral blood. This offers a valuable tool in the context of metastatic TNBC, in which tissue sampling is often challenging.
2024-10-31 | GSE270235 | GEO
Project description:Immunotherapies, including immune checkpoint inhibitors (ICI), have revolutionized the treatment of many cancers, producing significant improvements in survival in patients with many different cancers. However, the intended anti-tumor effects also result in a unique form of autoimmunity, known as immune-related adverse events (irAEs), which have emerged as a limiting factor for many immunotherapies. Cutaneous irAEs (cirAEs), the most frequently occurring ICI–related toxicities, have been associated with improved efficacy and survival but, in their severe forms, require systemic steroids and have in cases led to premature ICI discontinuation and fatality. There is a need for both robust biomarkers and adequate models that effectively predict which patients who develop irAEs may have improved outcomes. Using a microfluidic droplet technology that generates "mini" patient-derived organoids called MicroOrganoSpheres (MOSTM), we successfully generated skin MOS from skin biopsy samples in both healthy skin and tumor-involved skin that sustain the original patient skin immune microenvironment over three weeks. Using this model, we assessed skin cell toxicity and cytokine release in response to ICI and targeted therapies. Clinical responses were largely consistent with the skin and tumor MOS assay readouts, indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Matched pairs of patient melanoma and skin MOS showed good concordance with patient outcome indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Enrichment of genes associated with atopic dermatitis, vitiligo, and psoriatic dermatitis were observed in MOS generated from skin of an ICI-sensitive patient compared to the MOS generated from skin of an ICI-resistant patient. These results indicated that the skin MOS platform can potentially predict the dermatological toxicity of ICI. As the MOS assay can be completed within 12 days after biopsy acquisition, this novel technology may enable personalized medicine approaches by prediction of cirAEs and efficacy for individual patients.
2023-03-31 | GSE226869 | GEO
Project description:Targeting the PD-1/PD-L1 pathway has changed the landscape of cancer immunotherapy, revolutionizing the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell–inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that predict responsiveness to anti-PD-1/anti-PD-L1 monotherapy in a variety of tumor types. Here we analyze the association between these biomarkers and efficacy in 11 commonly used preclinical murine syngeneic models using a rodent surrogate antibody (muDX400) of pembrolizumab, a humanized monoclonal antibody against PD-1. Response to muDX400 treatment was broadly classified in these models into 3 categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune-cell infiltration and activation in the tumor microenvironment of muDX400 responsive tumors. Baseline and post-treatment genomic analysis showed an association between murine-GEP and TMB and response to muDX400 treatment. To better understand the limitations, predictive nature and role of these models in guiding treatment options at the bedside, we extended our analysis to investigate a canonical set of cancer and immune biology-related gene expression signatures, including signatures of angiogenesis, monocytic myeloid derived suppressor cell (mMDSC) and stromal/EMT/TGF-β biology previously shown to have potential negative impact on immunotherapy efficacy in the clinic. Finally, reverse translation studies were performed to evaluate the association between murine-GEP and preclinical efficacy with standard of care and anti-angiogenic combinations with muDX400 which show promising clinical activity. These efforts begin to elucidate which biological mechanisms can and cannot be appropriately and productively tested in these preclinical models to facilitate the development of rational orthogonal combination strategies with checkpoint blockade as well as the evaluation of underlying biological mechanisms associated with response in the clinic
2022-01-07 | GSE168846 | GEO