Immune Checkpoint Inhibitors in Human Glioma Microenvironment.
Ontology highlight
ABSTRACT:
SUBMITTER: Ghouzlani A
PROVIDER: S-EPMC8301219 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Immunotherapy has become a powerful clinical strategy in cancer treatment. Immune checkpoint inhibitors (ICIs) have opened a new era for cancer immunotherapy. Nowadays, the number of immunotherapy drug approvals has increased, with numerous treatment options in clinical and preclinical development. However, there remain some obstacles to improve the efficacy of ICIs further. The tumor immune microenvironment (TIME) consists of cancer cell, immune cells and cytokines, et cetera. The dynamics of TIME determine the efficacies of ICIs. Although the ICIs showed manageable toxicity, immune-related adverse effects (irAEs) are still unignorable for clinicians. Since some primary resistance mechanisms exist in TIME, ICIs can only show effects in individual cancer patients. Even for the patients who responded, acquired resistance will occur to neutralize the effect of ICIs. Understanding how to increase the response rates and overcome the resistance to various classes of ICIs is the key to improving clinical efficacy. Besides the novel ICIs in development, there are some approaches to establish combination therapies are underway to improve further the efficacies of ICIs in treating cancer patients. Here, we describe the complicated TIME and state quo of ICIs to prospect the future of ICIs in cancer treatment.
| S-EPMC7575936 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD-L1 expression on tumors, tumor-infiltrating lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.
| S-EPMC7469863 | biostudies-literature
Project description:Abstract This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness and safety of anti‐PD‐1 and anti‐PD‐L1 antibodies in the treatment of adults with diffuse glioma.
| S-EPMC6464918 | biostudies-literature
Project description:BACKGROUND AND AIMS:Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have clinical activity in hepatocellular carcinoma (HCC), but only a subset of patients respond to these therapies, highlighting a need for novel biomarkers to improve clinical benefit. HCC usually occurs in the setting of liver cirrhosis from chronic hepatitis B or C viral infection, but the effects of viral status on the tumor immune microenvironment and clinical responses to ICIs in HCC remains unclear. METHODS:We conducted a meta-analysis to estimate the objective response rates for PD-1/PD-L1 inhibitors in virally-infected and uninfected patients, and examined the effects of viral etiology on the tumor microenvironment using data from The Cancer Genome Atlas, as well as peripheral blood responses using an independent cohort of patients studied by mass cytometry (cytometry by time-of-flight (CyTOF)). RESULTS:Meta-analysis comparing objective response rates (ORR) between virally-infected and uninfected patients showed no clinically meaningful difference (absolute difference of ORR in virally-infected vs uninfected=-1.4%, 95%?CI: -13.5% to 10.6%). There was no relationship between viral etiology on features of the tumor immune microenvironment that are known to modulate responses to PD-1/PD-L1 inhibitors, and the tumor mutational burden was similar between virally-infected and uninfected HCC. RNA sequencing of tissue-resident T cell and B cell repertoires similarly showed no effect of viral status on their diversity. CyTOF analysis of peripheral blood specimens further demonstrated similar expression of immune-related markers in response to PD-1 inhibitor therapy in virally-infected and uninfected HCC. CONCLUSION:There is no significant effect of viral etiology on the tumor immune microenvironment in HCC, and viral status should not be used as a criterion to select patients for PD-1/PD-L1 therapy.
| S-EPMC7204805 | biostudies-literature
Project description:Background: Lung cancer has always been the most prevalent cancer. Lung adenocarcinoma (LUAD) is the most common lung cancer subtype and has a high tumor mutation rate. In addition to KRAS, EGFR, ALK, HER2, ROS1, and BRAF, which are known to have high mutation rates, we discovered some new mutated genes, such as catenin alpha-2 (CTNNA2), in LUAD patients treated with immune checkpoint inhibitors (ICIs). These mutant genes are potential therapeutic targets for LUAD. Methods: We analyzed a cohort of LUAD patients with somatic mutation and survival data in the Cancer Genome Atlas (TCGA) database and a cohort of LUAD patients receiving immune checkpoint inhibitors with clinical data and whole-exome sequencing (WES) mutation data to evaluate the role of CTNNA2 gene mutation in LUAD. In addition, CIBERSORT was used to analyze the immune characteristics of CTNNA2 wild-type patients and CTNNA2 mutant-type patients, and gene set enrichment analysis (GSEA) was employed for pathway enrichment analysis. The results were verified by downloading data regarding the drug sensitivity of LUAD cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results: We found that CTNNA2 mutation was associated with longer overall survival (OS) in LUAD patients. Analysis of the cohort from the Cancer Genome Atlas showed that patients with CTNNA2 mutation had more tumor neoantigens and a greater tumor mutation burden (TMB). Through further analysis of the tumor immune microenvironment, we found that in LUAD patients with CTNNA2 mutations, the gene expression levels of chemokine C-X-C motif chemokine 9 (CXCL9) and granzyme B (GZMB) were elevated, and the gene expression level of inhibitory receptor killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) was significantly reduced. These alterations might affect gene expression in macrophages, NK cells, and mast cell markers. In addition, LUAD patients with CTNNA2 mutation had a significantly increased number of mutations in DNA damage response (DDR) genes. The drug susceptibility results and gene set enrichment analysis showed that after CTNNA2 mutation occurred, changes were found in the DNA damage response pathway, the phosphoinositide 3-kinase (PI3K) pathway and others, indicating that CTNNA2 mutation can regulate the activation of PI3K and DDR pathways. Conclusion: Our findings provide novel insights into the underlying pathogenesis of LUAD. CTNNA2 mutation can change the immune microenvironment, thereby improving patient prognosis. The results also suggest that CTNNA2 may become a new biomarker and therapeutic target for LUAD in the future.
| S-EPMC8215613 | biostudies-literature
Project description:Pyroptosis is a proinflammatory programmed cell death pathway mediated by gasdermins. Exploring the role of pyroptosis can provide new insights into tumor malignancy. The most recent studies on pyroptosis have focused on tumor cells. However, the effects of pyroptosis on the tumor microenvironment (TME), immunotherapeutic responses, and efficacy have been neglected, especially in case of glioma. In this study, four independent glioma cohorts comprising 1,339 samples and a pan-cancer cohort comprising 10,535 tumor samples were analyzed. The relationships among pyroptosis status, prognosis, microenvironment cellular components, and clinical and biological phenotypes were investigated through the identification of pyroptosis subtypes, construction of a gasdermin-related prognostic index (GPI), and evaluation of immunological characteristics in glioma. The Genomics of Drug Sensitivity in Cancer database and "pRRophetic" package in R were used to estimate temozolomide (TMZ) sensitivity. The "Submap" package and external immunotherapy cohorts were used to investigate and confirm the role of GPI in response to and efficacy of immunotherapy in glioma. Finally, potential small-molecule compounds related to GPI were identified using the connectivity map database and mode-of-action analysis. We identified three different pyroptosis subtypes: cluster 1 (C1) characterized by a higher GPI, while cluster 2 (C2) and cluster 3 (C3) characterized by a lower GPI. The high GPI of C1 was associated with glioma progression and worse prognoses, whereas the low GPI of subtype C2 and C3 was associated with better prognoses. However, patients with high GPIs were found to be more sensitive to TMZ and immune checkpoint blockade than those with low GPIs. Furthermore, gasdermin D may be a principal potential biomarker and play key roles in pyroptosis-inducible therapy combined with immunotherapy in glioma. This study provides a clinical, biological, and molecular landscape of pyroptosis and suggests that pyroptosis of glioma cells may perform the dual function of promoting both tumorigenesis and antitumor immunity.
| S-EPMC9249059 | biostudies-literature
Project description:BackgroundThoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown.Materials and methodsPatients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non-small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma.ResultsNine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line.ConclusionSMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.
| S-EPMC9177113 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) have shown promising results in bladder cancer (BC). However, only some patients respond to ICIs. DNA repair defects (DDR) play an important role in the therapeutic response of bladder cancer. Therefore, we aimed to elucidate the association between ICIs in bladder cancer and ataxia telangiectasia mutated (ATM), a core component of the DNA repair system. From a collected immunotherapy cohort (n = 210) and The Cancer Genome Atlas (TCGA)-Bladder cancer cohort, which were both retrieved from publicly available resources, we performed a series of analyses to evaluate the prognostic value and potential mechanism of ATM in bladder cancer immunotherapy. We found that ATM-mutant (ATM-MT) bladder cancer patients derived greater benefit from ICIs [overall survival (OS), hazard ratio (HR) = 0.28, [95% confidence interval (CI), 0.16 to 0.51], P = 0.007] and showed a higher mutation load (P < 0.05) and immunogenicity (P < 0.05) than ATM-wild-type (ATM-WT) patients. The immune inflammatory response to antigenic stimulation, the regulation of the IFN pathway and the macrophage activation pathway were significantly enriched in the ATM-MT group (NES > 1, P < 0.05), while insulin-like growth factor receptor signaling pathways and vasculogenesis were significantly downregulated (NES < -1, P < 0.05). ATM mutation significantly upregulated the number of DNA damage repair pathway gene mutations (P < 0.05). ATM mutations resulted in increased bladder cancer sensitivity to 29 drugs (P < 0.05), including cisplatin and BMS-536924, an IGF-1R inhibitor. Our results demonstrate the importance of ATM as a prognostic signature in bladder cancer and reveal that ATM may impact the effects of ICIs by acting on the tumor immune microenvironment.
| S-EPMC7456912 | biostudies-literature
Project description:Few studies were conducted investigating the immunological profiles in gastrointestinal stromal tumors (GIST). Adaptive and innate immune cells are present in the tumor microenvironment, indicating GIST as inflamed tumors. In addition, murine models suggested a potential interaction between immune components and imatinib. In this retrospective study, the GIST immunological profile was investigated through in silico analysis and immunohistochemistry (IHC), exploring the basis for immunotherapy approaches. Gene expression profiles (GEP) from 31 KIT/PDGFRA-mutant GIST were analyzed to evaluate the tumor microenvironment and immunotherapy predictive signatures such as the expanded IFN-γ-induced immune signature (EIIS) and the T-cell-inflamed signature (TIS). GEP and IHC supported the presence of immune infiltrate in GIST, with dominance of CD4+ and CD8+ T cells and M2 macrophages showing a remarkable similarity with melanoma microenvironment. The EIIS genes were expressed in most of GIST samples and positively correlated with PD-L1 abundance (p < .0001). Co-expression was also found between PD-L1 and CD8A (p < .0001) or CD8B (p = .0003). Moreover, the median TIS score for GIST was between the 65th and 70th percentile of the Cancer Genome Atlas dataset, in the same range of tumors responding to anti-PD-1/PD-L1. Analysis of the Gene Expression Omnibus database GIST samples pre- and post-treatment confirmed that imatinib downregulates PD-L1 and IRF1 expression through the inhibition of KIT and PDGFRA, thus contributing to counteract the suppressed adaptive immune response against GIST. The presence of a rich immune infiltrate in GIST along with the presence of TIS and EIIS suggests that GIST may benefit from immunotherapy along with tyrosine kinase inhibitors.
| S-EPMC6685519 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) therapy has significantly progressed the treatment of bladder cancer (BLCA). Multiple studies have suggested that specific genetic mutations may serve as immune biomarkers for ICB therapy. Additionally, the nuclear receptor corepressor 1 (NCOR1) gene is a new player in the field of immune tolerance and the development of immune cells. In the ICI-treated-cohort, NCOR1 mutations may be used as a biomarker to predict the prognosis of BLCA patients receiving ICIs. The overall survival (OS) of the NCOR1-mutant (NCOR1-MT) group was significantly longer than that of NCOR1-wild-type (NCOR1-WT) group (P = 0·031; HR [95%CI]: 0·25 [0·12-0·52]). In the TCGA-BLCA-cohort, compared with NCOR1-WT, NCOR1-MT was associated with known predictors of ICB therapy efficacy, such as higher tumor mutational burden (TMB), neoantigen load and the number of mutations in the DNA damage-repair pathway. In addition, NCOR1-MT tumors had highly infiltrating TILs, activated antitumor immunity, and a high expression of immune-related genes, suggesting that NCOR1 mutations may serve as a potential biomarker to guide ICB therapy in BLCA.
| S-EPMC7982737 | biostudies-literature