Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma.

Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies.

Brain macrophage development, diversity and dysregulation in health and disease.

Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages that infiltrate the brain under various disease conditions. The vast heterogeneity of these cells has been elucidated over the last decade using revolutionary multiomics technologies. As such, we can now start to define these various macrophage populations according to their ontogeny and their diverse functional programs during brain development, homeostasis and disease pathogenesis. In this review, we first outline the critical roles played by brain macrophages during development and healthy aging. We then discuss how brain macrophages might undergo reprogramming and contribute to neurodegenerative disorders, autoimmune diseases, and glioma. Finally, we speculate about the most recent and ongoing discoveries that are prompting translational attempts to leverage brain macrophages as prognostic markers or therapeutic targets for diseases that affect the brain.

Exosomal lncRNA HOTAIR induces PDL1+ B cells to impede anti-tumor immunity in colorectal cancer.

Regulatory B cells (Bregs) contribute to tumor immunosuppression. However, how B cells acquire their regulatory features in tumors remain unclear. Exosomes are important messengers that transmit tumor information to remodel tumor immunity. Here we revealed that tumor-derived exosomes drive Bregs to suppress anti-tumor immunity by delivering long non-coding RNAs (lncRNAs). HOTAIR was screened by lncRNA profiling in both colorectal cancer (CRC)-derived exosomes and infiltrating B cells. Tumor-derived HOTAIR polarized B cells toward a regulatory feature marked by programmed cell death-ligand 1 (PDL1) in CRC, and induced PDL1+ B cells to suppress CD8+ T cell activity. Exosomal HOTAIR bound to and protected pyruvate kinase M2 (PKM2) against ubiquitination degradation, resulting in STAT3 activation and PDL1 expression. Results from CRC patients showed a positive correlation between exosomal HOTAIR and tumor-infiltrating PDL1+ B cells. These findings reveal how B cells acquire PDL1-dominant regulatory feature in CRC, implying the clinical significance of exosomal therapy targeting HOTAIR.

Relationship Between Dietary Fiber and Vitamin C Intake and Oral Cancer.

Background: Dietary fiber and vitamin C has been reported to play a possible role in tumorigenesis. However, few studies have estimated their association with oral cancer risk. In this project, we investigated the relationship between dietary fiber and vitamin C and oral cancer risk in adults in Southern China. Methods: 382 patients newly diagnosed with oral cancer were matched to 382 hospital derived controls by frequency matching in age and sex. Pre-diagnostic consumption of dietary fiber and vitamin C intake were measured through food frequency questionnaire. Association between nutrients intake and oral cancer risk were evaluated by logistic regression. OR value and 95% confidence interval was calculated. Results: Intake of dietary fiber and vitamin C was significantly lower in oral cancer patients (8.15 g/day) than in control participants (8.88 g/day). Increased dietary fiber or vitamin C intake was linked to a decreased incidence of OC after adjustment of age, marital status, residence, BMI, occupation, education, tobacco smoking, alcohol consumption and family history of cancer Ptrend < 0.001). Compared with the lowest tertile, the adjusted OR of the top tertile of dietary fiber was 0.47 (95 % CI 0.32, 0.68). While the adjusted OR of the highest tertile was 0.60 (95 % CI 0.42, 0.87) compared with the lowest tertile of vitamin C. Conclusions: Dietary intake of fiber and vitamin C were lower in oral cancer patients than in control participants. Dietary fiber and vitamin C were inversely related to risk of oral cancer risk.

Association Between Dietary Fatty Acid Pattern and Risk of Oral Cancer.

Objective: To investigate the association between dietary fatty acid (FA) patterns and the risk of oral cancer. Method: A case-control study which included 446 patients with oral cancer and 448 controls subjects was conducted in Southeast China. A structured food frequency questionnaire was used to assess the dietary FA consumption before cancer diagnosis. FA patterns were identified using the principal component analysis, and the relationship between the dietary FA patterns and oral cancer was analyzed by logistic regression. Results: General differences in FA intake were observed between the patient and control groups. The intakes of saturated FAs (SFAs) C14:0, C16:0, C18:0, and monounsaturated FA C18:1 were higher in the patient group than the control group (p < 0.001). Four FA patterns were derived by principal component analysis. The "SFA" pattern, "Polyunsaturated FA" pattern, "Monounsaturated FA" pattern, and "Medium- and long-chain FA" pattern, which could explain 75.7% of the variance of the dietary FA intake, were submitted to logistic regression analysis. A positive association was observed between the "SFA" pattern and oral cancer risk. Compared with the lowest quartile score, the OR of the highest quartile score was 3.71 (95%CI: 2.31, 5.94, P trend < 0.001) in the multivariate logistic regression model. No significant association was found among the other three patterns and oral cancer risk. Conclusions: General differences in dietary FA intake were observed between patients with oral cancer and controls. A positive association between the "SFA" pattern and risk of oral cancer was observed after adjusting for potential confounders.

Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion.

Immunoregulatory B cells impede antitumor immunity through unknown features and mechanisms. We report the existence of leucine-tRNA-synthase-2 (LARS2)-expressing B cell (LARS B) subset with a transforming growth factor-ß1 (TGF-ß1)-dominant regulatory feature in both mouse and human progressive colorectal cancer (CRC). Of note, LARS B cells exhibited a leucine nutrient preference and displayed active mitochondrial aminoacyl-tRNA biosynthesis. They were located outside the tertiary lymphoid structure and correlated with colorectal hyperplasia and shortened survival in CRC patients. A leucine diet induced LARS B cell generation, whereas LARS B cell deletion by Lars2 gene ablation or leucine blockage repressed CRC immunoevasion. Mechanistically, LARS2 programmed mitochondrial nicotinamide adenine dinucleotide (NAD+) regeneration and oxidative metabolism, thus determining the regulatory feature of LARS B cells in which the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was involved. We propose a leucine-dieting scheme to inhibit LARS B cells, which is safe and useful for CRC therapy.

Chimeric antigen receptor clustering via cysteines enhances T-cell efficacy against tumor.

Chimeric antigen receptor (CAR) T-cell therapy achieves great success for hematological malignancies. However, clinical trials have revealed some limitations in both improving the efficacy and reducing the relapse, which calls for innovative strategies to engineer more powerful CAR-T cells. Promoting the formation of CAR clusters provides an alternative approach and potentially improves current CAR T-cell therapy against cancers. Here, we generated CARCys-T cells using a 4-1BB-derived hinge region including 11 cysteines residues. The cysteines in the hinge were found to facilitate CARCys clustering upon antigen stimulation and promote the antitumor activity of CAR-T cells. Compared with most conventionally used CAR-T cells with CD8α-derived hinge (CARconv-T cells), CARCys-T cells exhibited larger diameter of CAR clusters and enhanced antigen-specific tumor lysis both in vitro and in vivo. In addition, the CARCys-mediated enhancement could be applied to HER2, CD19 as well as GPC3-targeted CAR-T cells. More importantly, CARCys-T cells showed potent antitumor efficacy in clinically relevant patient-derived primary tumor cells and organoids. Thus, the novel hinge containing 11 cysteines provides a promising strategy to facilitate CAR clustering and maximize anti-tumor activity of CAR-T cells, which emphasizes the importance of CAR clustering to improve CAR T-cell therapy in the clinic.

A novel prognostic score based on systemic inflammatory biomarkers for patients with oral squamous cell carcinoma.

OBJECTIVE: To explore the prognostic value of systemic inflammatory biomarkers (albumin/globulin ratio [AGR], neutrophil/lymphocyte ratio [NLR], and platelet/lymphocyte ratio [PLR]) in patients with oral squamous cell carcinoma (OSCC), and further develop a novel prognostic score (AGR-NLR). METHODS: A large-scale prospective study enrolling 792 eligible patients from December 2002 to June 2018 was carried out at the First Affiliated Hospital of Fujian Medical University. Three multivariate Cox regression models were performed to assess the association of overall survival (OS) with systemic inflammatory biomarkers, quantified by Akaike information criterion (AIC). Then, a novel AGR-NLR score was established and incorporated into a prognostic nomogram. RESULTS: In the univariate analysis, the increased AGR was associated with a reduced risk of death. Conversely, the higher NLR and PLR, the worse the OS. In the multivariate Cox regression models, AGR and NLR were stably independent prognostic indicators in all models, with Model 2 showing a lowest AIC (AGR: HR = 0.56, 95%CI: 0.41-0.78; NLR: HR = 1.80, 95%CI: 1.07-3.04). Then, a novel AGR-NLR score was established, which showed a more excellent performance than either AGR or NLR alone (area under curve [AUC]: 0.589, 0.559, and 0.556, respectively). The C-index of the nomogram based on AGR-NLR was superior to that of traditional TNM staging system (C-index: 0.658 versus. 0.596, p < .001). Similar results were also showed by decision curve analysis, indicating the nomogram had more positive net benefit compared to TNM staging system. CONCLUSION: The novel AGR-NLR score is strongly associated with outcome in patients with OSCC and could be serve as a useful tool to accurately predict the OS of OSCC patients.

[Association between hypertension and oral cancer prognosis in non-smoking and non-drinking women].

OBJECTIVE: To explore the association between hypertension and prognosis of oral cancer patients in non-smoking and non-drinking women. METHODS: From September 2010 to February 2019, 362 non-smoking and non-drinking female patients with pathologically confirmed oral cancer were recruited and followed up in the First Affiliated Hospital of Fujian Medical University. The patients were divided into hypertension group and non-hypertensive group, and the Kaplan-Meier method was performed to calculate the cumulative survival rate. The survival curve was tested by the log-rank method for differences between the two groups. Cox proportional regression model was utilized to explore the prognostic factors. 1∶1 propensity score matching was applied in order to verify the above findings. Stratified analysis was used to explore the prognosis of oral cancer treated by different method and fish intake between two groups respectively. RESULTS: The Cox proportional hazards model showed that the risk of death of hypertension patients was 1.976 times than nonhypertensive patients(95%CI 1.003-3.890), the risk of death for patients with lymph node metastasis was 2.938 times than patients without metastasis(95%CI 1.318-6.551), the risk of death for patients underwent surgery combined with adjuvant therapy was 0.454 times than surgery alone(95%CI 0.236-0.875). After propensity score matching, the Cox proportional hazard model showed that the risk of death for patients with hypertension was 2.987 times than non-hypertensive patients(95%CI 1.050-8.497). The result of stratified analysis showed that the risk of death for non-hypertensive patients with surgery combined with adjuvant therapy was 0.233 times than patients with surgery alone(95%CI 0.085-0.643) and the risk of death in patients with hypertension who consumed fish ≥3 times/week was 0.020 times higher than that in women with oral cancer who consumed fish<3 times/week(95%CI 0.001-0.392). CONCLUSION: Hypertension is an independent prognostic factor for oral cancer in non-smoking and non-drinking women. Non-hypertensive patients underwent surgery combined with adjuvant therapy can reduce the risk of death and the increase of fish intake can improve the prognosis of hypertensive female oral cancer patients.

[Correlation between serum iron level and overall survival of oral cancer].

OBJECTIVE: To explore the correlation between serum iron(Fe) and the overall survival of oral cancer. METHODS: Patients with oral cancer who met the inclusion criteria in the Department of Oral and Maxillofacial Surgery of the First Affiliated Hospital of Fujian Medical University from January 2010 to April 2017 were collected. The average age was(57.12±13.94) years old, including 489 males(65.46%), 258 females(34.54%) and 564 cases of squamous cell carcinoma(77.90%). Overall survival rates were calculated by Kaplan-Meier method. Survival difference was compared by log-rank test. Cox regression model was used to estimate the hazard ratio(HRs) and 95% confidence intervals(95%CIs). RESULTS: The distributions of serum iron level were non-normal distribution(P<0.001), and the serum iron level is expressed as 13.9(10.3, 17.8)µmol/L in M(P25, P75). According to X-tile, the optimal cut-off value of serum iron was 15.3 µmol/L, used as a criterion to group patients. The result showed that the mortality risk of patients with oral cancer in high serum iron level(Fe>15.3 µmol/L) was 0.72 times of patients in lower one(Fe≤15.3 µmol/L)(95%CI 0.52-0.99). Stratified analysis suggested that serum iron was a good predictor of patients with oral cancer aged 60 years(HR=0.62, 95%CI 0.39-0.99), male(HR=0.66, 95%CI 0.44-0.98), with TNM stage I-II(HR=0.42, 95%CI 0.20-0.88) and squamous cell of pathological type(HR=0.69, 95%CI 0.49-0.97). CONCLUSION: Serum iron is closely related to the overall survival of oral cancer, patients with high serum iron have a lower risk of death.

A dynamic prognostic nomogram to predict the benefit from surgical treatment modality for patients with laryngeal squamous cell carcinoma.

BACKGROUND: Although nonsurgical treatment strategy is increasingly adopted in patients with locoregionally advanced laryngeal squamous cell carcinoma (LSCC), survival disparities were reported between surgical treatment modality and organ preservation protocols, highlighting the great importance for accurate patients' selection. METHOD: This secondary analysis used data from the Surveillance, Epidemiology, and End Results database between 2010 and 2015 with follow-up data up to 2018. We developed and validated a dynamic prognostic nomogram for overall survival (OS) in 4237 patients with LSCC and subgroup of 2087 patients with locoregionally advanced laryngeal squamous cell carcinoma (LALSCC). Based on the total risk score derived from the dynamic nomogram, two well-matched risk groups (i.e., low- and high-risk) were created via X-tile software and 1-to-1 propensity score matching (PSM); surgical treatment modality was compared with nonsurgical one in each risk group. RESULTS: A more accurate and convenient dynamic prognostic nomogram based on age, marital status, T category, N category, M category, tumor size, and tumor differentiation was developed and validated, of which the predictive performance was superior to that of TNM staging system. For high-risk LALSCC selected by the dynamic nomogram, after 1-to-1 PSM, significantly improved OS was observed in patients with receiving surgical treatment compared to those receipt of nonsurgical management (restricted mean survival time at 36-month: 26.6 vs 22.7, p < 0.001; restricted mean survival time at 60-month: 36.7 vs 31.0, p = 0.003). CONCLUSION: We establish and validate a more accurate and convenient dynamic prognostic nomogram for patients with LSCC, which may predict the benefit from surgical treatment modality for patients with high-risk LALSCC.

Prognostic value of preoperative lymphocyte-to-monocyte ratio in oral cancer patients and establishment of a dynamic nomogram.

OBJECTIVE: To assess the association of preoperative lymphocyte-to-monocyte ratio (LMR) and overall survival (OS) in patients with oral cancer and develop a dynamic nomogram for individualized survival prediction. METHOD: The prognostic value of LMR was evaluated in a large-scale cohort with 651 postoperative patients with oral cancer between January 2010 and December 2017. Propensity score-matched (PSM) analysis and inverse probability of treatment weighting (IPTW) analysis were performed to further verify the prognostic value of LMR. A dynamic nomogram was then developed based on the LMR and clinicopathological features, and its predictive performance and clinical utility were evaluated. RESULTS: A high LMR was significantly associated with better OS of patients with oral cancer (HR = 0.65; 95% CI = 0.44-0.98). The similar association was also observed in the PSM and IPTW analyses. Moreover, compared with TNM staging system, the dynamic nomogram based on the LMR exhibited more excellent predictive performance (0.72 versus 0.64, p < .001), with calibration curves (1,000 bootstrap resamples) suggesting good match between the actual and predicted probabilities. Decision curve analyses (DCAs) showed a more significant positive net benefit in the practical ranges of threshold probabilities using the dynamic nomogram. CONCLUSION: Preoperative LMR may serve as an easily accessible and non-invasive prognostic biomarker for predicting the prognosis of patients with oral cancer. A dynamic nomogram based on the LMR may show more convenience in survival prediction for patients with oral cancer. Further future studies are warranted to confirm our findings.

Prognostic value of preoperative systemic inflammation response index in patients with oral squamous cell carcinoma: Propensity score-based analysis.

BACKGROUND: The aim of the study was to elucidate the relationship between systemic inflammation response index (SIRI) and the prognosis of postoperative oral squamous cell carcinoma (OSCC) patients. METHODS: The prognostic value of SIRI was evaluated in a prospective cohort consisting of 535 OSCC patients with surgical resection. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses were used to further verify the prognostic value of SIRI. RESULTS: Patients with a higher SIRI had a significantly increased risk of mortality compared with those with a low SIRI (HR [hazard ratio]: 1.60, 95% CI [confidence interval]: 1.04-2.47). The similar association pattern was observed following PSM (HR: 1.97, 95% CI: 1.14-3.40) and IPTW (HR: 1.70, 95% CI: 1.29-2.24) analyses. Of note, receiving postoperative chemotherapy resulted in a 72% of decreased risk of death among patients with a higher SIRI (HR: 0.28, 95% CI: 0.08-0.95). Additionally, a novel prognostic nomogram, based on TNM stage, tumor differentiation, and SIRI, demonstrated superior accuracy for the prediction of overall survival than that of the seventh edition of the AJCC staging system. CONCLUSION: Preoperative SIRI may be a valuable tool for prediction of survival of OSCC patients.

Selenoprotein genetic variants may modify the association between serum selenium and oral cancer risk.

OBJECTIVE: The relationship between selenium (Se) and oral cancer is still controversial, and the selenoprotein genes play crucial roles in selenium metabolism. We aim to investigate the potential effect of selenoprotein genes (including GPx and TXNRD) in the association of serum Se with oral cancer risk. METHODS: A case-control study including 235 oral cancer cases and 406 controls from September 2011 to December 2018 was conducted in Fujian, China. The peripheral blood samples were obtained from each participant. Genotyping was performed by MassARRAY system, and serum Se levels were measured by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Compared with the lowest tertile of Se concentration, those with Se levels in the third tertile were associated with the lower risk of oral cancer (OR = 0.228; 95% CI: 0.135, 0.384). After additional adjustment for genetic risk score (GRS, derived from selenoprotein genetic variants), the model demonstrated the superior goodness of fit. When stratified by GRS, the negative correlation of serum Se was more pronounced among those with low risk (i.e., lower GRS). Moreover, there is a multiplicative interaction between serum Se and GRS for the risk of oral cancer (p = .001). CONCLUSIONS: The present study suggests that serum Se levels may be significantly associated with oral cancer risk, yet the association may be modified by the effects of selenoprotein genetic variants.

TLR1/TLR2 signaling blocks the suppression of monocytic myeloid-derived suppressor cell by promoting its differentiation into M1-type macrophage.

Myeloid derived suppressor cells (MDSCs) play a key role in tumor immunosuppressive microenvironment, which helps tumors avoid immune destruction. Blocking the suppressive activities of MDSCs could be a promising strategy to enhance the effect of anti-tumor immunotherapies. In this study, we found that TLR1/TLR2 expression predicted favorable prognosis of lung cancer patients. In the related mice tumor model, TLR1/TLR2 activation by synthetic bacterial lipoprotein (BLP), a TLR1/2 agonist, greatly inhibited tumor growth and selectively decreased monocytic MDSCs (M-MDSCs). Furthermore, BLP treatment redirected M-MDSC differentiation towards M1 macrophage through JNK pathway, and thus blocked the suppressive activity of M-MDSCs in a TLR2-dependent manner. Therefore, our data demonstrated that TLR2 could be a promising biomarker and a potential immunotherapeutic target for lung cancer.

Identification and immunological evaluation of novel TLR2 agonists through structure optimization of Pam3CSK4.

Toll-like receptor 2 (TLR2) is a bridge between innate immunity and adaptive immunity. TLR2 agonists have been exploited as potential vaccine adjuvants and antitumor agents. However, no TLR2 agonists have been approved by FDA up to now. To discover drug-like TLR2 selective agonists, a novel series of Pam3CSK4 derivatives were designed based on the crystal structure of hTLR2-hTLR1-Pam3CSK4 complex, synthesized and evaluated for their immune-stimulatory activities. Among them, 35c was identified as a murine-specific TLR2 agonist, while 35f was a human-specific TLR2 agonist. Besides, 35d (human and murine TLR2 agonist) showed TLR2 agonistic activity comparable to Pam3CSK4, which included: elevated IL-6 expression level (EC50 = 83.08 ±â€¯5.94 nM), up-regulated TNF-α and IL-6 mRNA expression and promoted maturation of DCs through activating the NF-κB signaling pathway. TLRs antibodies test showed that 35a and 35d were TLR2/1 agonists, while 35f was a TLR2/6 agonist.

The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy.

BACKGROUND: PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. METHODS: The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival. RESULTS: The distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-γ level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-γ induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-γ-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-γ level. By combining the relative expression of the listed IFN-γ-induced genes, IFN-γ score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies. CONCLUSION: Our study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-γ is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-γ score aggregated from the expressions of the listed IFN-γ-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.

Molecular subgroups and B7-H4 expression levels predict responses to dendritic cell vaccines in glioblastoma: an exploratory randomized phase II clinical trial.

Dendritic cell (DC)-based vaccination is a promising approach for active-specific immunotherapy, but is currently of limited efficacy. The safety and effectiveness of a DC vaccine (DCV) loaded with glioblastoma stem cell-like (GSC) antigens was assessed in glioblastoma multiforme (GBM) patients. In this double-blind, placebo-controlled phase II clinical trial, 43 GBM patients were randomized after surgery at a 1:1 ratio to receive either DCV (n = 22) or normal saline placebo (n = 21). Overall survival (OS) and progression-free survival (PFS) were analysed. Participants were stratified into different molecular subgroups based on the mutation (MT) status of isocitrate dehydrogenase (IDH1/2) and telomerase reverse transcriptase (TERT). Plasma cytokine levels, tumor-infiltrating lymphocyte numbers and immune co-inhibitory molecules PD-L1 and B7-H4 were also assessed. Multivariate Cox regression analysis revealed that DCV treatment significantly prolonged OS (p = 0.02) after adjusting for IDH1 and TERT promoter MT and B7-H4 expression, primary vs recurrent GBM. Among IDH1wild type (WT) TERTMT patients, DCV treatment significantly prolonged OS (p < 0.01) and PFS (p = 0.03) and increased plasma levels of cytokines CCL22 and IFN-γ compared with placebo. Patients with low B7-H4 expression showed significantly prolonged OS (p = 0.02) after DCV treatment. Therefore, IDH1WTTERTMT and low B7-H4 expression identified subgroups of GBM patients more responsive to GSC DCV-based specific active-immunotherapy.

TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia.

Gliomas, the most common primary neoplasms in the brain, are notorious for their ability to evade the immune response. Despite microglial infiltration in gliomas, expression of MHC class II molecules in those microglia is compromised. Here, we report that Toll-like receptor 2 (TLR2) activation downregulated expression of MHC class II molecules in microglia in an orthotopic murine glioma model. TLR2-induced microglial impairment hindered the proliferation and activation of CD4+ T cells, which facilitated glioma immune evasion. TLR2-induced downregulation of MHC class II molecules was caused by suppression of the master regulator of MHC class II molecule transcription, Ciita TLR2 activation triggered downstream MAPK/ERK1/2 signaling and loss of histone H3 acetylation at Ciita promoters, which in turn inhibited Ciita expression. In glioblastoma tissues, various endogenous TLR2 ligands, including the heat shock proteins that are endogenous TLR2 ligands, were upregulated, a response that correlated with CIITA inhibition. Thus, TLR2 promotes glioma immune-system evasion. These results advance our understanding of microglia as antigen-presenting cells in the context of glioma. In the glioma tumor microenvironment, TLR2 activation of microglia induces downregulation of microglial MHC class II expression. Impaired MHC class II expression limits T-cell-dependent antitumor immunity. Cancer Immunol Res; 6(10); 1220-33. ©2018 AACR.