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Immune Checkpoint Inhibitors in Human Glioma Microenvironment.

ABSTRACT: Gliomas are the most common primary brain tumors in adults. Despite the fact that they are relatively rare, they cause significant morbidity and mortality. High-grade gliomas or glioblastomas are rapidly progressing tumors with a very poor prognosis. The presence of an intrinsic immune system in the central nervous system is now more accepted. During the last decade, there has been no major progress in glioma therapy. The lack of effective treatment for gliomas can be explained by the strategies that cancer cells use to escape the immune system. This being said, immunotherapy, which involves blockade of immune checkpoint inhibitors, has improved patients' survival in different cancer types. This novel cancer therapy appears to be one of the most promising approaches. In the present study, we will start with a review of the general concept of immune response within the brain and glioma microenvironment. Then, we will try to decipher the role of various immune checkpoint inhibitors within the glioma microenvironment. Finally, we will discuss some promising therapeutic pathways, including immune checkpoint blockade and the body's effective anti-glioma immune response.

SUBMITTER: Ghouzlani A

PROVIDER: S-EPMC8301219 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Immune Checkpoint Inhibitors in Human Glioma Microenvironment.

Ghouzlani Amina A Kandoussi Sarah S Tall Mariam M Reddy Konala Priyanka KP Rafii Soumaya S Badou Abdallah A

Frontiers in immunology 20210709

Gliomas are the most common primary brain tumors in adults. Despite the fact that they are relatively rare, they cause significant morbidity and mortality. High-grade gliomas or glioblastomas are rapidly progressing tumors with a very poor prognosis. The presence of an intrinsic immune system in the central nervous system is now more accepted. During the last decade, there has been no major progress in glioma therapy. The lack of effective treatment for gliomas can be explained by the strategies ...[more]

PMID: 34305910

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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.

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.

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.

Dataset Information

Immune Checkpoint Inhibitors in Human Glioma Microenvironment.

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Immune Checkpoint Inhibitors in Human Glioma Microenvironment.

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