A single-cell atlas of immune heterogeneity in anti-PD1-treated non-small cell lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE243013 | GEO | 2025/01/28
REPOSITORIES: GEO
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Project description:Lack of reliable predictive biomarkers is a major limitation of combination therapy with chemotherapy and anti-PD-1 therapy (chemo-immunotherapy). The increase of peripheral blood (PB) CD8+ T cells expressing CX3CR1, a marker of differentiation, correlates with response to anti-PD-1 therapy; however, the predictive and prognostic value of T-cell CX3CR1 expression during chemo-immunotherapy remains elusive. Here, we evaluated the utility of PB CX3CR1+CD8+ T cells as a predictive correlate of response to chemo-immunotherapy in non-small cell lung cancer (NSCLC) patients. At least 10% increase of the CX3CR1+ subset in circulating CD8+ T cells from baseline (CX3CR1 score) was associated with response to chemo-immunotherapy at 6 weeks (p = 0.0382) and 9 weeks (p = 0.0045). Sensitivity, specificity, positive and negative predictive value of at least 10% increase of the CX3CR1 score was 83.3%, 88.2%, 83.3% and 88.2%, respectively with 86.2% overall accuracy of predicting response at 9 weeks. Furthermore, at least 10% increase of the CX3CR1 score correlated with improved overall (p = 0.0105) and progression-free survival (p = 0.0265). Combined T-cell receptor (TCR) sequencing of tumor tissue and single-cell RNA/TCR sequencing of longitudinal PB samples from a patient who received a long-term benefit from chemo-immunotherapy demonstrated that circulating clonally expanded CD8+ T cells were terminal effector T cells expressing high levels of CX3CR1, and contained frequent tumor-infiltrating T-cell colonotypes early-on post treatment. Collectively, these findings suggest the potential utility of T-cell CX3CR1 expression as a dynamic blood-based biomarker during the course of chemo-immunotherapy and a marker to identify frequent tumor-infiltrating lymphocyte repertoires.
2023-04-05 | GSE213902 | GEO
Project description:The endpoint of this study was to prospectively validate the prognostic significance of fecal Akk in advanced NSCLC patients treated with first or second line ICI. We performed RNA sequencing to compare transcriptomic profiles of the different groups.
2021-08-20 | GSE182328 | GEO
Project description:We formulate and analyse a mathematical model describing immune response to avasculartumour under the influence of immunotherapy and chemotherapy and their combinations aswell as vaccine treatments. The effect of vaccine therapy is considered as a parametricperturbation of the model. In the case of a weak immune response, neither immunotherapy norchemotherapy is found to cause tumour regression to a small size, which would be below theclinically detectable threshold. Numerical simulations show that the efficiency of vaccinetherapy depends on both the tumour size and the condition of immune system as well as on theresponse of the organism to vaccination. In particular, we found that vaccine therapy becomesmore effective when used without time delay from a prescribed date of vaccination after surgeryand is ineffective without preliminary treatment. For a strong immune response, our modelpredicts the tumour remission under vaccine therapy. Our study of successive chemo/immuno,immuno/chemo and concurrent chemoimmunotherapy shows that the chemo/immunosequence is more effective while concurrent chemoimmunotherapy is more sparing.
2020-01-14 | MODEL2001140002 | BioModels
Project description:Enhancer RNA (eRNA) is critical element with highly specific pattern in regulatory network across infiltrated immune cells. Herein we developed eRNA immunotherapy signature (eRIS) based on these eRNAs which significantly connected with anti-tumor immune cells. The eRIS was highly correlated with objective response rate (ORR) to immune checkpoint blockade (ICB) treatment, and was significantly increased in these patients who benefit from ICB treatment. By integrating with pharmacogenomics datasets, we screened hundreds of eRIS associated anti-cancer drugs, which showed potential in improving immunotherapy with cancer type or subtype-specific specific manner. We further characterized one drug, the HDAC inhibitor vorinostat, in isocitrate dehydrogenase mutant gliomas, and found Combining vorinostat with anti-PD-1 could decrease tumor size and increase survival time in vivo by enhancing abundance of anti-tumor immune cells. We further provided eRIS markers which showed strong capacity of eRIS in predicting immunotherapy response in clinical samples or animal models. Our study revealed the potential utility of eRIS to improve immunotherapy response by identifying combinational drugs, that provide novel insights to benefit patients in certain cancer or subtypes.
2024-05-01 | GSE248513 | 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:Background: A pressing challenge in treating non-small cell lung cancer (NSCLC) lies in the significant variability of patient responses to immunotherapy. This issue underscores the critical need for innovative predictive models that can navigate beyond conventional biomarkers to enhance patient outcomes, particularly by addressing immunotherapy resistance or responsiveness. Hypothesis: We hypothesize that an integrated multi-omics approach will uncover interactions within the NSCLC tumor immune microenvironment (TIME) and identify novel biomarkers that are predictive of individual immunotherapy responses, thus aiding in the development of a robust personalized treatment planning model. Objective: To develop a predictive model for NSCLC immunotherapy response/resistance by identifying new biomarkers using co-detection by indexing (CODEX) and Digital Spatial Profiling of whole transcriptome atlas (DSP-WTA). Methods: We utilized a multi-omics approach, combining CODEX for spatial mapping of protein expression at the single-cell level and DSP-WTA for comprehensive transcriptomic insights from the cell types identified by CODEX. This methodology facilitated a detailed examination of the TIME in NSCLC samples from patients undergoing first-line immunotherapy. Results: Our analysis identified three cell types, proliferating tumor cells, granulocytes, and vessels, that are associated with resistance to immunotherapy. The high proportion of these cell types demonstrated a hazard ratio (HR) of 3.8 (p = 0.004) in the training cohort (N = 33) and 1.8 (p = 0.05) in the validation cohort (N = 35). In the response cell type model, higher levels of M1 macrophages, M2 macrophages, and CD4 T cells returned a HR of 0.4 (p = 0.019) in the training set and 0.49 (p = 0.036) in the validation set. Gene signatures related to these cell types also predicted outcomes with high accuracy. The resistant gene model, which included 8 genes associated with epithelial-mesenchymal transition (EMT) and cell migration showed a HR of 5.3 (p < 0.001) in the training set and 2.2 (p = 0.036) in the validation set. The response gene model, consisting of 8 genes associated with immunomodulation, had an HR of 0.22 (p = 0.005) in the training set and 0.38 (p = 0.034) in the validation set. Conclusion: This research highlights the potential of a multi-omics strategy in advancing NSCLC treatment toward precision oncology. By offering insights into the TIME and unveiling novel biomarkers, our model seeks to define resistance and to improve prediction of response to treatment.
2024-08-22 | GSE271689 | GEO
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.
2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress
Project description:Introduction: Immune checkpoint inhibitors(ICIs) targeting programmed cell death protein 1 (PD1) confer significant survival benefits to patients with non-small cell lung cancer (NSCLC). However, there remains a substantial unmet need to identify therapeutic approaches to overcome resistance and provide benefits to these patients. High-dose ascorbic acid (AA) acts synergistically with many standard anticancer treatments. However, little is known about the effect of high-dose AA on improving the efficacy of anti-PD1 inhibitors in NSCLC. This study aimed to elucidate the effects of high-dose AA on anti-PD1 immunotherapy in NSCLC. Methods: The combined effects of high-dose AA and anti-PD1 were investigated using a coculture model of H460 cells and CD8+ T cells and an LLC1 lung cancer syngeneic mouse model. To investigate the molecular mechanism, tumor tissues from mice were analyzed by comprehensive proteomic profiling using nano-LC-ESI-MS/MS. Results: Pretreatment with a high dose of AA led to enhanced the sensitivity to the cytotoxicity of CD8+ T cells derived from healthy donor for H460 cells. Additionally, the combination of anti-PD1 and high-dose AA significantly increased CD8+ T cell cytotoxicity in H460 cells. The combination of anti-PD1 and high-dose AA showed dramatic antitumor effects in a syngeneic mouse model of lung cancer by significantly reducing tumor growth and increasing CD8+ T cell-dependent cytotoxicity and macrophage activity. Comprehensive protein analysis confirmed that high-dose AA in anti-PD1-treated tumor tissues enhanced the antitumor effects by regulating various immune-related mechanisms, including the B cell and T cell receptor signaling pathways, Fc gamma R-mediated phagocytosis, and natural killer (NK) cell-mediated cytotoxicity. Discussion: Our results suggest that high-dose AA may be a promising adjuvant to potentiate the efficacy of anti-PD1 immunotherapy.
2025-01-15 | PXD059688 | Pride
Project description:Phenotyping of tumors into hot, altered, or cold based on assessment of only T-cell infiltration in static tumor biopsies provides suboptimal prediction of immunotherapy response. In vivo dynamic mechanisms within the tumor microenvironment such as tumor angiogenesis and leukocyte trafficking also play a central role in modulating anti-tumor immunity and therefore immunotherapy response. Here, we report novel tumor immune microenvironment (TiME) phenotyping in vivo in patients with non-invasive spatially-resolved cellular-level imaging based on endogenous contrast. Investigating skin cancers as a model, with reflectance confocal microscopy (RCM) imaging, we determined four major phenotypes with variable prevalence of vasculature (Vasc) and inflammation (Inf) features: VaschiInfhi, VaschiInflo, VascloInfhi and Vascmed/hiInflo. The VaschiInfhi phenotype correlates with high immune activation, exhaustion, and vascular signatures while VaschiInflo with endothelial anergy and immune exclusion. Automated quantification of TiME features demonstrates moderate-high accuracy and correlation with corresponding gene expression. Prospectively analyzed response to topical immunotherapy show highest response in VascloInfhi, and reveals the added value of vascular features in predicting treatment response.
2022-07-03 | GSE181037 | GEO
Project description:N6-methyladenosine (m6A) is the most printed and prevalent mRNA modification, which was verified to be closely correlated with cancer occurrence and progression. As m6A demethlyase, the dysregulation of ALKBH5 was observed in various cancer. However, the role and underlying machinery of ALKBH5 in NSCLC pathogenesis, especially the chemo-resistance was poorly elucidated. The current study indicated that ALKBH5 was decreased during paclitaxel (PTX) resistant process and its down-regulation usually implied poor prognosis of NSCLC patients. Over-expression of ALKBH5 in PTX-resistant cells could suppressed cell proliferation and enhanced chemo-sensitivity. Whereas, knockdown of ALKBH5 exerted opposite effect, which further supported the tumor suppressive role of ALKBH5. Over-expression of ALKBH5 also could reverse the EMT process in PTX-resistant cancer cells. Mechanistically, data of RNA-seq, Real-time PCR and western blotting indicted that CEMIP, also known as KIAA1199, may be the downstream target of ALKBH5. And ALKBH5 could negatively regulated the CEMIP level by decreasing its mRNA stability. Collectively, current data demonstrated that ALKBH5/CEMIP axis modulates the EMT process in NSCLC, which in turn regulates chemo-sensitivity of cancer cells to PTX.
2024-03-12 | GSE243199 | GEO