Glioblastoma Multiforme (GBM) is the most common malignant primary brain tumor. Despite aggressive multimodality treatment it remains one of the most challenging and intractable cancers (1]. While current standard of care treatment for GBM is maximal safe surgical resection, systemic chemotherapy with Temozolimide (TMZ), and radiation therapy, the current prognosis of GBM patients remains poor, with a median overall survival of 12-15 months (2, 3). Therefore, other treatments are needed to provide better outcomes for GBM patients. Immunotherapy is one of the most promising new cancer treatment approaches. Immunotherapy drugs have obtained regulatory approval in a variety of cancers including melanoma (4), Hodgkin lymphoma (5), and non-small cell lung cancer (6). The basis of immunotherapy in cancer treatment is linked to stimulating the immune system to recognize cancer cells as foreign, thereby leading to the eventual elimination of the tumor. One form of immunotherapy utilizes vaccines that target tumor antigens (7), while other approaches utilize T-cells in patients to stimulate them to attack tumor cells (8). Despite intensive efforts all approaches have not been overtly successful (9), suggesting that we need to better understand the underlying biology of tumor cells and their environment as they respond to immunotherapy. Recent studies have elucidated epigenetic pathway regulation of GBM tumor expansion (10), suggesting that combined epigenetic pathway inhibition with immunotherapy may be feasible. In this review, we discuss current GBM clinical trials and how immune system interactions with epigenetic pathways and signaling nodes can be delineated to uncover potential combination therapies for this incurable disease.

/pdf/immunotherapy-and-epigenetic-pathway-modulation-in-57c2giiqi4.pdf

Immunotherapy and Epigenetic Pathway Modulation in Glioblastoma Multiforme.

Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene. We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs. We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p < 0.001, R = 0.28) and its association increased in the recurrent tumor (p  < 0.001, R = 0.86). TSs reflected the tissue-level patterns of association between the two genes (p < 0.01, R = 0.59, n = 20). A scRNAseq data of a TS revealed the TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5. GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.

/pdf/co-expression-of-cancer-driver-genes-idh-wildtype-k7fdkqwe7y.pdf

Co-expression of cancer driver genes: IDH-wildtype glioblastoma-derived tumorspheres

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a poor prognosis despite multimodal interventions. For brain tumors, immunotherapy has not yet fully proved their potential. The central nervous system has historically been regarded as an immune privileged organ, throwing doubt on application of immunotherapy to GBM. However, growing evidences suggest that immune cells can traverse the blood-brain barrier and affect immune responses in the brain. Although immunotherapy by programmed cell death protein 1 (PD-1) blockade has dramatically improved the survival rate of some types of cancer patients, its application to GBM still needs further investigation. To improve efficacy of immunotherapy, there have been many attempts for finding effective combination partner in several types of tumors. We hypothesized that TMZ could work synergistically with PD-1 blockade to generate a robust antitumor response against GBM. Here, we evaluated therapeutic responses of PD-1 blockade and its combination with temozolomide (TMZ) in mouse GBM model. PD-1 blockade remarkably showed long-term antitumor effects, and combined use of TMZ further improved survival rate. However, distinct working mechanisms operated in these two therapeutic strategies. Anti-PD-1 monotherapy significantly augmented the number of tumor-infiltrating lymphocytes and protected them from exhaustion. In comparison, TMZ combination abrogated these effects, suggesting that superior therapeutic efficacy did not originated from increased immune responses. Microarray experiments revealed that anti-PD-1 and combination groups differentially converted transcriptional programs, particularly emphasized by mutually exclusive functional annotation by ImmuneSigDB gene sets. Moreover, tumor rechallenge study showed that immunologic memory was generated only in the anti-PD-1 monotherapy group. Although TMZ did not facilitate anti-PD-1-mediated immune response or memory function, these data suggest that combined treatment of anti-PD-1 and TMZ exert robust antitumor efficacy with therapeutic benefits in GBM. In addition, our data suggest possibility of immunotherapy to be added in standard treatment modalities of GBM.

/pdf/immu-16-effect-of-anti-pd-1-therapy-combination-on-2jo72loqcw.pdf

Immu-16. effect of anti-pd-1 therapy combination on temozolomide in mouse glioblastoma.

Exth-28. 5-aminolevulinic acid-based photodynamic therapy of glioblastoma tumorsphere and acquired resistance by tumor mesenchymal stem-like cells

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Immu-16. effect of anti-pd-1 therapy combination on temozolomide in mouse glioblastoma.

Exth-28. 5-aminolevulinic acid-based photodynamic therapy of glioblastoma tumorsphere and acquired resistance by tumor mesenchymal stem-like cells