Immune mechanism for the treatment of GBM with PD-1 inhibitors

Glioblastoma (GBM) is a common primary malignant brain tumor in adults, with an average survival of 16 months to 20 months after standard treatmentA recent clinical trial of a recurrent GBM metastasis of procedural cell death-1 (PD-1) inhibitors showed that only 8% of patients responded to PD-1 inhibitors (pembrolizumab or nivolumab)Analyzing the molecular characteristics of gene molecules that affect the effectiveness of PD-1 inhibitors in GBM patients, such as Junfei Zhao of columbia University's Department of Systems Biology in New York, Usain, is published in the March 2019 issue of Nature Medicinethe study methods
the researchers conducted retrospective analysis of 66 adult GBM patients, who were treated with PD-1 inhibitors when the tumor recursIf the following criteria are met, it is considered to have an answer to treatment: after PD-1 inhibitor treatment, tissue samples taken during surgery basically show only inflammatory response and tumor-free cells, associated with false progression;the relationship between demographic data and clinical performance and the therapeutic response to PD-1 inhibitors using single variable survival analysisTo avoid potential confusion, after excluding patients with a survival of less than 6 months, a strong correlation was found between PD-1 inhibitor response and overall survival, and an average survival of PD-1 inhibitor respondents was 14.3 months, higher than 10.1 months for those without answers of PD-1 inhibitorsThis effect was stronger in patients with a survival period of less than 6 months, with the median survival of the respondents being 15.5 months, while the median survival of non-respondents was 5.7 monthsThere was no significant difference between the median survival period and the initial diagnosis time of the two groups of patients and the start time of PD-1 inhibitor treatmentresultsanalysis of 58 full exon group and 38 transcription groups in 17 patients, as well as the cancer genome of 39 patients, showed that the median 47 (14 to 83) non-sysym mutations in 33 tumors were typical GBMThere are no more non-synonymous single nucleotide variants (nsSNVs) than non-resonant tumors in baseline response tumorsIn the sample of the patient's first operation, the non-responder's nsSNV median was 40, while the respondent was 26The difference syme of non-whole stoids of resonated tumors and non-response tumors was not statistically significantSimilarly, the prediction of new epitopal loads in the human leukocyte antigen Class I (HLA-I) had similar results in both groups, with a bit value of 45 in the non-response group and a bit value of 35 (P-0.41) in the response groupNo significant association was found between HLA heterojoinivity and immunotherapy response or survival There was no significant difference in purity between the two groups of tumors assessed the mutations (nsSNVs and indels) that were significantly rich in transsexual and non-responsive tumors, and identified a total of 11 IDH1 R132G/H mutant tumors, of which 4 appeared in respondents and 7 in non-responders In 45 idh1 wild tumor patients, 23 PTEN mutations were found in 32 non-responders, while only 3 were mutants in 13 respondents The frequency of mutations in PTEN in non-resonating tumor patients was significantly higher than in patients with transhuman tumors In the Cancer Genome Map (TCGA), 154 of the 458 tumors of IDH1 wild GBM had a mutation rate of about 33 ;P the concentration of TEN mutations in non-responders was significantly higher than predicted the rich fractions of the PI3K AKT pathway for each tumor in single-sample genetic analysis (ssGSEA), a significant increase in PI3K AKT pathway activity in PTEN-mutated non-responsive tumors was observed (t-test P-0.049) No differences were found between CD274 mRNA expression and non-responsive tumors Of the 13 respondents, the MAPK pathway component (including BRAF and PTPN11) had four mutations, compared with only 1 mutation in 32 non-respondents Taking into account the rare mutation of MAPK pathway in IDH1 wild GBM (the mutation rate in the TCGA database was 7.8%), the frequency of mutations in mapK pathway genes in responsive tumors was significantly higher than predicted Similarly, the mutation of the MAPK pathway was significantly enriched among respondents tumors of non-responders and responders showdifferent evolutionary patterns Compared with pre-treatment of PD-1 inhibitors, post-treatment tumor-specific mutations accounted for a higher proportion of 2 cases (20 and 53) non-responders, indicating that a classic linear model of tumor evolution was followed The tumors of the 2 respondents (55 and 71) were more similar to the branch model Pre-treatment advantage cloning of PD-1 inhibitors no longer exists after treatment, indicating that its changes and evolutionary patterns are related to treatment In patients 55, three misidentified mutations (MYPN R409H, UBQLN3 R159W, and CYP27B1 G194E) occurred prior to PD-1 inhibitor treatment One of the mutations (CYP27B1 G194E) is highly expressive and may produce new antigens In the other two respondents (71 and 101), a misnometry mutation (FNIP1 T409M and TCF12 A605S) was missed after immunotherapy, which was highly expressed and a new antigen was possible By identifying T-cell antigen receptor (TCR) and immunoglobulin RNA sequences, the evolution of lymphocytes in tumors was tracked, and in 7 patients, the cloning diversity of T lymphocytes increased significantly compared to non-responders in 7 patients (P-0.024) There is a similar protoscocin of immunoglobulin RNA sequences, indicating a similar reaction in B lymphocytes (P-0.048) expression subtypes (front wall type, interstitial type, and classical subtype) were not associated with tumor response By analyzing the enrichment difference soutcomes of 9292 gene sets of MSigDB, the first gene concentration splinters of the pre-treatment and regulated T(Treg) cell-related gene sets of PD-1 inhibitors can be observed Enrichment analysis showed that gene-regulated Treg cells were more active in non-resonant tumors After immunotherapy, the gene set associated with immunosuppression is active in responsive tumors, including FOXP3 and STAT3 signals, as well as immune escape signals After PD-1 inhibitor treatment, immunohistamytification imaging of 5 tumors (2 respondents, 3 non-responders) did not find CD4-FOXP3-Treg cells, indicating that the above-mentioned FOXP3 expression cells originated from another cell type To study its origins, the transcription spectrum of 9,000 cells in 3 cases of GBM was analyzed, including a PTEN mutant tumor Cell enrichment associated with the Treg cell in PTEN mutant tumors was consistent with the PTEN mutant samplefound in TCGA Through topological data analysis, three main cell groups were identified: small glial cells, active proliferating tumor cells (Ki67 plus) and tumor cells with migration markers (CD44 plus) were highly correlated with the PTEN mutant CD44 plus tumor subgroup in the study of the effects of PTEN mutation on the formation of tumor immune microenvironment, analysis of RNA-seq data from 172 samples of TCGA found that the PTEN mutation was significantly correlated with the transcriptional characteristics of the above-mentioned foxp3 and the tumor purity was low Analysis of the level of single-sample immersion of 24 immune cells by ssGSEA showed that PTEN mutations were significantly correlated with elevated levels of macrophages, small glial cells and neutrophils in tumor microenvironments When the relationship between PTEN mutation and tumor microenvironment structure was observed by quantitative multiple immunofluorescent fluorescence (qmIF), the dyeing of 17 patients (7 non-responders and 10 respondents) of The tumor specimens of Formarin fixed paraffin encapsulation was found that the overall CD68-macrophhagy leachate level of PTEN mutant tumor was high, but the difference was not statistically significant The classification of PTEN mutant tumors showed that the density of CD68-HLA-DR macrophages increased significantly The CD3-T cell density in PTEN wild-type samples after PD-1 inhibitor treatment increased significantly compared to pre-treatment, while the PTEN mutant samples did not experience this change Similar trends were observed in CD3-CD8-and CD3-CD8-T cells Compared with the PTEN wild type, the PTEN mutant type has a stronger aggregation between tumor cells prior to immunotherapy PTEN wild patients are more dense after immunotherapy However, this effect can be reversed in PTEN mutants conclusions in general, the researchers found that immunoresponders treated with PD-1 inhibitors had significantly longer survival spans than non-responders Genomics and transcriptomics analysis showed that PTEN mutations associated with immunosuppressive expression characteristics were significantly enriched in non-responders, while MAPK pathway changes were enriched in responders Resonant tumors are associated with branch patterns that evolved from the elimination of new epitope, to T-cell cloning diversity and differences in tumor microenvironment The authors note that PD-1 inhibitors did not improve the overall survival of GBM patients, but some genotyping still has a chance to benefit and needs further exploration.