Promotion of an Antitumor Immune Program by a Tumor-specific, Complement-activating Antibody.

Tumor-targeting Abs can be used to initiate an antitumor immune program, which appears essential to achieve a long-term durable clinical response to cancer. We previously identified an anti-complement factor H (CFH) autoantibody associated with patients with early-stage non-small cell lung cancer. We cloned from their peripheral B cells an mAb, GT103, that specifically recognizes CFH on tumor cells. Although the underlying mechanisms are not well defined, GT103 targets a conformationally distinct CFH epitope that is created when CFH is associated with tumor cells, kills tumor cells in vitro, and has potent antitumor activity in vivo. In the effort to better understand how an Ab targeting a tumor epitope can promote an effective antitumor immune response, we used the syngeneic CMT167 lung tumor C57BL/6 mouse model, and we found that murinized GT103 (mGT103) activates complement and enhances antitumor immunity through multiple pathways. It creates a favorable tumor microenvironment by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells, enhances Ag-specific effector T cells, and has an additive antitumor effect with anti-PD-L1 mAb. Furthermore, the immune landscape of tumors from early-stage patients expressing the anti-CFH autoantibody is associated with an immunologically active tumor microenvironment. More broadly, our results using an mAb cloned from autoantibody-expressing B cells provides novel, to our knowledge, mechanistic insights into how a tumor-specific, complement-activating Ab can generate an immune program to kill tumor cells and inhibit tumor growth.

Hypoxia-inducible PRMT2 addiction in glioblastomas.

Hypoxia-inducible transcription factors (HIFs) are key transcription factors for cellular response to low oxygen levels. However, the specific mediators responsible for activating downstream transcription are not well characterized. We previously identified Protein Arginine methyltransferase 2 (PRMT2), a highly expressed methyltransferase in glioblastoma multiforme, as a transcription co-activator. And we established a connection between PRMT2-mediated histone H3R8 asymmetric methylation (H3R8me2a) and transcription activation. Here we find that PRMT2 is activated by HIF1α under hypoxic conditions. And we demonstrate that PRMT2 and its H3R8me2a activity are required for the transcription activation of a significant subset of hypoxia-induced genes. Consequently, the inactivation of PRMT2 suppresses hypoxia-induced glioblastoma cell migration, attenuates tumor progression, and enhances chemotherapeutic sensitivity in mouse xenograft models. In addition, our analysis of clinical glioma specimens reveals a correlation between PRMT2 protein levels, HIF1α abundance, and an unfavorable prognosis. Our study establishes HIF1α-induced PRMT2 as a critical modulator in the activation of hypoxia-related transcriptional programs, ultimately driving malignant progression.

Complement factor H: a novel innate immune checkpoint in cancer immunotherapy.

The elimination of cancer cells critically depends on the immune system. However, cancers have evolved a variety of defense mechanisms to evade immune monitoring, leading to tumor progression. Complement factor H (CFH), predominately known for its function in inhibiting the alternative pathway of the complement system, has recently been identified as an important innate immunological checkpoint in cancer. CFH-mediated immunosuppression enhances tumor cells' ability to avoid immune recognition and produce an immunosuppressive tumor microenvironment. This review explores the molecular underpinnings, interactions with immune cells, clinical consequences, and therapeutic possibilities of CFH as an innate immune checkpoint in cancer control. The difficulties and opportunities of using CFH as a target in cancer immunotherapy are also explored.

Impact of HER2-low status for patients with early-stage breast cancer and non-pCR after neoadjuvant chemotherapy: a National Cancer Database Analysis.

PURPOSE: To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting. METHODS: We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan-Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses. RESULTS: For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72-0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85-0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79-0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86-0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77-0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83-0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61-1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85-1.45), p = 0.44]. CONCLUSION: In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR.

Nomograms for predicting overall survival and cancer-specific survival of endometrioid ovarian carcinoma: A retrospective cohort study from the SEER database.

OBJECTIVE: Endometrioid ovarian cancer (EnOC) accounts for approximately 10%-15% of epithelial ovarian cancer cases. There are no effective tools for predicting the prognosis of EnOC in clinical work. The aim of this study was to construct and validate a nomogram to predict overall survival and cancer-specific survival (CSS) in patients with EnOC. METHODS: Data regarding patients diagnosed with primary EnOC between 2004 and 2019 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. LASSO Cox regression and Cox regression analyses were performed to screen for prognostic factors, which were used to construct nomograms. In addition, we performed subgroup analyses of the prognostic value of chemotherapy and lymph node surgery. RESULTS: In total, 3957 patients with primary EnOC were included in the analysis: 2770 in a training cohort and 1187 in a validation cohort. Age, stage, grade, lymph node surgery, and race were significantly and independently correlated with overall survival and CSS. Nomograms were constructed to predict 3- and 5-year overall survival and CSS. Nomograms have good predictive ability and clinical practicability. Subgroup analysis showed that lymph node surgery improved the prognosis of patients with EnOC (P < 0.05) except for patients with grade III-IV and Stage I disease (overall survival P = 0.272, CSS P = 0.624). Chemotherapy did not improve survival time in most patients (P > 0.05) except for patients with grade I-II and Stage II-IV disease (overall survival P = 0.008, CSS P = 0.046). CONCLUSION: We constructed predictive nomograms and a risk classification system to evaluate overall survival and CSS in EnOC patients. For most patients with EnOC, chemotherapy did not improve the prognosis. In contrast to chemotherapy, lymph node surgery improved prognosis in most patients with EnOC.

Bcl2l1 Deficiency in Osteoblasts Reduces the Trabecular Bone Due to Enhanced Osteoclastogenesis Likely through Osteoblast Apoptosis.

Bcl2l1 (Bcl-XL) belongs to the Bcl-2 family, Bcl2 and Bcl2-XL are major anti-apoptotic proteins, and the apoptosis of osteoblasts is a key event for bone homeostasis. As the functions of Bcl2l1 in osteoblasts and bone homeostasis remain unclear, we generated osteoblast-specific Bcl2l1-deficient (Bcl2l1fl/flCre) mice using 2.3-kb Col1a1 Cre. Trabecular bone volume and the trabecular number were lower in Bcl2l1fl/flCre mice of both sexes than in Bcl2l1fl/fl mice. In bone histomorphometric analysis, osteoclast parameters were increased in Bcl2l1fl/flCre mice, whereas osteoblast parameters and the bone formation rate were similar to those in Bcl2l1fl/fl mice. TUNEL-positive osteoblastic cells and serum TRAP5b levels were increased in Bcl2l1fl/flCre mice. The deletion of Bcl2l1 in osteoblasts induced Tnfsf11 expression, whereas the overexpression of Bcl-XL had no effect. In a co-culture of Bcl2l1-deficient primary osteoblasts and wild-type bone-marrow-derived monocyte/macrophage lineage cells, the numbers of multinucleated TRAP-positive cells and resorption pits increased. Furthermore, serum deprivation or the deletion of Bcl2l1 in primary osteoblasts increased apoptosis and ATP levels in the medium. Therefore, the reduction in trabecular bone in Bcl2l1fl/flCre mice may be due to enhanced bone resorption through osteoblast apoptosis and the release of ATP from apoptotic osteoblasts, and Bcl2l1 may inhibit bone resorption by preventing osteoblast apoptosis.

Adipose-derived mesenchymal stem cell exosomes ameliorate spinal cord injury in rats by activating the Nrf2/HO-1 pathway and regulating microglial polarization.

As of now, there are no satisfactory treatments for spinal cord injury (SCI), so new therapeutic approaches are necessary to be explored. Adipose-derived mesenchymal stem cell exosomes (ADMSC-Exo), delightfully, show remarkable therapeutic effects. Therefore, we try to investigate the effects and mechanisms of ADMSC-Exo on SCI, as well as to provide novel approaches for the treatment of SCI. Adipose-derived mesenchymal stem cells (ADMSC) were isolated from rats and then exosomes (Exo) were extracted from the cells. The extracted Exo were identified by flow cytometry, transmission electron microscopy and nanoparticle tracking analysis (NTA). Then, the SCI rat model was established by the spinal cord impactor and injected with 200 µl PBS or Exo into their tail veins at 30 min, 24 h, and 48 h after surgery. The rats in the Control group and Exo group only exposed the spine. Motor function recovery was assessed on days 0, 7, 14, 21, and 28; histopathological changes and apoptosis levels in spinal cord tissues were observed by HE staining and TUNEL staining; the levels of inflammatory cytokines TNF-a, IL-6, and MCP-1 in spinal cord tissues were measured by ELISA; the expression levels of iNOS, IL-12, Arg1, and Mrc1 in spinal cord tissues were detected by qRT-PCR; and Nrf2, HO-1, and NQO1 protein expression in spinal cord tissues were detected by Western blot. ADMSC-Exo were successfully isolated and identified. ADMSC-Exo significantly relieved SCI and promoted motor function recovery in SCI rats. Moreover, ADMSC-Exo inhibited the expression of both inflammatory factors in the spinal cord tissues and M1 microglia, promoted the expression of M2 microglia, and activated the Nrf2/HO-1 pathway. Altogether, ADMSC-Exo can not only ameliorate SCI, but also promote the motor function recovery of rats. And the mechanism of ADMSC-Exo improving SCI may be achieved by activating Nrf2/HO-1 pathway and microglial polarization.

Feasibility, safety, and efficacy of task-oriented mirrored robotic training on upper-limb functions and activities of daily living in subacute poststroke patients: a pilot study.

BACKGROUND: Robotic training with high repetitions facilitates upper-limb movements but provides fewer benefits for activities of daily living. Integrating activities of daily living training tasks and mirror therapy into a robot may enhance the functional gains of robotic training. AIM: The aim of this study was to investigate the feasibility, safety, and efficacy of the task-oriented mirrored upper-limb robotic training on the upper-limb functions and activities of daily living of subacute poststroke patients. DESIGN: This study is a single-blinded, active-controlled pilot study. SETTING: The study was carried out at rehabilitation outpatient clinic and ward. POPULATION: A total of 32 subacute poststroke patients were enrolled in the study. METHODS: The enrolled patients were allocated into two groups in a ratio of 1:1. The experimental group received 4 weeks of task-oriented mirrored upper-limb robotic training, consisting of five sessions of 30-minute duration, along with 30 minutes of conventional training. The control group only received 60 minutes of conventional training. The outcome measures were the Fugl-Meyer Assessment Scale for Upper Extremity, Modified Barthel Index, Stroke Self-Efficacy Scale, System Usability Scale, and Quebec User Evaluation with Assistive Technology. RESULTS: All patients completed the full training sessions without significant adverse events related to robotic training. The task-oriented mirrored upper-limb robotic training led to increased Fugl-Meyer Assessment Scale for Upper Extremity (difference: 10.38 points, P<0.001) and Modified Barthel Index (difference: 18.38 points, P<0.001) scores, both of which exceeded the minimal clinically important difference. Intergroup analysis showed significantly higher improvements in the Fugl-Meyer Assessment Scale for Upper Extremity total scores, shoulder, wrist, and hand scores; and Modified Barthel Index scores in the experimental group than in conventional training (all P<0.05). Both groups showed significant improvements in Stroke Self-Efficacy Scale scores after the intervention (both P<0.001), but without a statistically significant intergroup difference (P>0.05). Participants in the experimental group scored an average usability perception score of 74.74 (good) and an average satisfaction score of four or more out of five. CONCLUSIONS: In general, task-oriented mirrored upper-limb robotic training appears feasible and safe for subacute poststroke rehabilitation, facilitating the recovery of upper-limb functions and activities of daily living. CLINICAL REHABILITATION IMPACT: Task-oriented mirrored upper-limb robotic training shows promise for future clinical rehabilitation and clinical trials involving subacute poststroke patients.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Antitumor Immune Mechanisms of the Anti-Complement Factor H Antibody GT103.

Development of novel therapeutic antibodies that not only kill tumor cells but modulate the adaptive immune response has the potential to produce long term anticancer immunity and a durable clinical response. We previously reported the discovery of anti-complement factor H (CFH) autoantibodies in patients with lung cancer that were associated with early-stage disease and exceptional outcomes. The human mAb GT103, produced from a single CFH autoantibody-expressing B cell of a patient with lung cancer, recognizes a conformationally distinct epitope on tumor cells, kills tumor cells, and inhibits tumor growth in animal studies. Recent experiments have shown that GT103 restructures the tumor microenvironment and initiates a robust antitumoral adaptive immune response. The current study further elucidates several mechanisms by which GT103 kills tumor cells and drives the immune program. Here we show GT103 has specificity for tumor cells without binding to native soluble CFH or normal tissues. GT103 causes complement C3 split product deposition on tumor cells in vitro and in vivo, triggers antibody-dependent cellular phagocytosis, and increases translocation of the danger-associated molecular pattern molecule calreticulin to the plasma membrane. We also demonstrate that GT103 causes B-cell activation in vitro and in vivo, and that GT103 antitumor activity in vivo is B-cell dependent. The complex mechanism of GT103, a tumor-specific antibody that kills tumor cells and stimulates an immune response, supports further development of this human-derived antibody as a novel therapeutic option for patients with lung cancer.

Mindin (SPON2) Is Essential for Cutaneous Fibrogenesis in a Mouse Model of Systemic Sclerosis.

Systemic sclerosis is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as systemic sclerosis has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor SNAI1 is overexpressed in the epidermis of patients with systemic sclerosis, and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (SPON2) in fibrogenesis. Mindin is produced by SNAI1 transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.

Anticancer Benefit of Metformin in Patients With Early-Stage Pancreatic Cancer: A Retrospective Cohort Study.

Background: Epidemiologic studies have produced conflicting results on the effects of metformin on pancreatic cancer. This study aimed to observe and analyze whether metformin use is associated with better prognosis in pancreatic cancer. Materials and Methods: In this retrospective cohort study, all baseline data were retrieved from The Chinese Medicine Information Retrieval System (https://dc.wzhospital.cn/vpn/index.html) of The First Affiliated Hospital of Wenzhou Medical University. Survival data were collected by follow-up visits and medical records. Overall survival was the primary endpoint, while progression-free survival and disease-free survival were secondary endpoints. Progression or recurrence was assessed with radiologic images. Results: Seventy-six metformin users and 92 metformin nonusers diagnosed with pancreatic cancer from 2012 to 2020 in this hospital were enrolled. The adjusted hazard ratio for overall survival for metformin users was 0.50 (95% confidence interval = 0.33-0.76), where median overall survival was 16.0 months for metformin users versus 11.5 months for metformin nonusers. The protective effect was also found by analyzing progression-free survival (adjusted hazard ratio = 0.39, 95% confidence interval = 0.18-0.86) and disease-free survival (adjusted hazard ratio = 0.30, 95% confidence interval = 0.14-0.68). In the subgroup analysis, metformin use had a statistically significant association with prolongation of survival in stage I to II pancreatic cancer patients (hazard ratio = 0.47, 95% confidence interval = 0.25-0.91), but not for advanced tumor stage (hazard ratio for IV stage = 0.62, 95% confidence interval = 0.33-1.19), after adjustment for other risk factors. Conclusion: Metformin use is related to favorable survival outcomes of pancreatic cancer, especially in early tumor stage.

Cuproptosis-related modification patterns depict the tumor microenvironment, precision immunotherapy, and prognosis of kidney renal clear cell carcinoma.

Background: Due to the different infiltration abundance of immune cells in tumor, the efficacy of immunotherapy varies widely among individuals. Recently, growing evidence suggested that cuproptosis has impact on cancer immunity profoundly. However, the comprehensive roles of cuproptosis-related genes in tumor microenvironment (TME) and in response to immunotherapy are still unclear. Methods: Based on 43 cuproptosis-related genes, we employed unsupervised clustering to identify cuproptosis-related patterns and single-sample gene set enrichment analysis algorithm to build a cuproptosis signature for individual patient's immune cell infiltration and efficacy of immune checkpoint blockade (ICB) evaluation. Then, the cuproptosis-related genes were narrowed down using univariate Cox regression model and least absolute shrinkage and selection operator algorithm. Finally, a cuproptosis risk score was built by random survival forest based on these narrowed-down genes. Results: Two distinct cuproptosis-related patterns were developed, with cuproptosis cluster 1 showing better prognosis and higher enrichment of immune-related pathways and infiltration of immune cells. For individual evaluation, the cuproptosis signature that we built could be used not only for predicting immune cell infiltration in TME but also for evaluating an individual's sensitivity to ICBs. Patients with higher cuproptosis signature scores exhibited more activated cancer immune processes, higher immune cell infiltration, and better curative efficacy of ICBs. Furthermore, a robust cuproptosis risk score indicated that patients with higher risk scores showed worse survival outcomes, which could be validated in internal and external validation cohorts. Ultimately, a nomogram which combined the risk score with the prognostic clinical factors was developed, and it showed excellent prediction accuracy for survival outcomes. Conclusion: Distinct cuproptosis-related patterns have significant differences on prognosis and immune cell infiltration in kidney renal clear cell carcinoma (KIRC). Cuproptosis signature and risk score are able to provide guidance for precision therapy and accurate prognosis prediction for patients with KIRC.

LRIG2 promotes glioblastoma progression by modulating innate antitumor immunity through macrophage infiltration and polarization.

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor with poor clinical outcomes. Immunotherapy has recently been an attractive and promising treatment of extracranial malignancies, however, most of clinical trials for GBM immunotherapy failed due to predominant accumulation of tumor-associated microglia/macrophages (TAMs). RESULTS: High level of LRIG2/soluble LRIG2 (sLRIG2) expression activates immune-related signaling pathways, which are associated with poor prognosis in GBM patients. LRIG2/sLRIGs promotes CD47 expression and facilitates TAM recruitment. Blockade of CD47-SIRPα interactions and inhibition of sLRIG2 secretion synergistically suppress GBM progression in an orthotropic murine GBM model. CONCLUSIONS: GBM cells with high level LRIG2 escape the phagocytosis by TAM via the CD47-SIRPα axis, highlighting a necessity for an early stage of clinical trial targeting LRIG2 and CD47-SIRPα as a novel treatment for patients with GBM.

Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of matricellular protein Mindin.

Preservation of a small population of cancer stem cells (CSCs) within a heterogeneous carcinoma serves as a paradigm to understand how select cells in a tissue maintain their undifferentiated status. In both embryogenesis and cancer, Snail has been correlated with stemness, but the molecular underpinning of this phenomenon remains largely ill-defined. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-epithelial-mesenchymal transition function for the transcription factor Snail in maintaining the stemness of epidermal keratinocytes. Snail-expressing cells secrete the matricellular protein Mindin, which functions in an autocrine fashion to activate a Src-STAT3 pathway to reinforce their stem/progenitor phenotype. This pathway is activated by the engagement of Mindin with the leukocyte-specific integrin, CD11b (ITGAM), which is also unexpectedly expressed by epidermal keratinocytes. Interestingly, disruption of this signaling module in human cSCC attenuates tumorigenesis, suggesting that targeting Mindin would be a promising therapeutic approach to hinder cancer recurrence.

Association between the LINC00673 rs11655237 C> T polymorphisms with cancer risk in the Chinese population: A meta-analysis.

OBJECTIVES: The present study aimed to conduct a meta-analysis of previously published studies in order to clarify the association of long noncoding RNA (lncRNAs) LINC00673 rs11655237 C> T polymorphism with cancer risk. DESIGN: Systematic review and meta-analysis. SETTING: Electronic databases of PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and Wanfang Database were used to search relevant studies. Studies published up to October 20, 2019 were included. The included studies were assessed in the following genetic model: allelic model, homozygote model, Heterozygote model, dominant model, recessive model. Data syntheses were conducted using STATA 12.0. PARTICIPANTS: Participants with various types cancers were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Odds ratio (ORs) and 95% confidence interval (CIs) were calculated to assess the risk of tumor. RESULTS: Seven articles including 7 case-control studies, 7423 cases and 11,049 controls were adopted for meta-analysis. Our result demonstrated that LINC00673 rs11655237 C> T was related to the cancer among all model including allelic model (T vs C: pooled OR = 1.24, 95% CI = 1.16-1.41, P < .001), homozygous model (TT vs CC: pooled OR=1.54, 95% CI = 1.36-1.76, P < .001), heterozygous model (CT vs CC: pooled OR=1.24, 95% CI = 1.16-1.32, P < .001), dominant model (CT + TT vs CC: pooled OR=1.28, 95% CI = 1.20-1.36, P < .001) and recessive model (TT vs CT+ CC: pooled OR=1.42, 95% CI = 1.25-1.61, P < .001). Subgroup analysis also demonstrated that polymorphisms at this site also increased the risk of neuroblastoma. CONCLUSIONS: Our results find that rs11655237 contributed to occurrence of cancer in all models in Chinese population.

A 9-LncRNA Signature for Predicting Prognosis and Immune Response in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. To assign patients into different risk categories, cytogenetic abnormalities and genetic mutations have been widely applied to the prognostic stratification of DLBCL. Increasing evidence has demonstrated that deregulated epigenetic modifications and long noncoding RNAs (lncRNAs) contribute to the initiation and progression of DLBCL. However, specific lncRNAs that affect epigenetic regulation and their value in predicting prognosis and therapy response remain uncertain. Here, 2,025 epigenetic-related genes were selected, and 9 lncRNAs (PRKCQ-AS1, C22orf34, HCP5, AC007389.3, APTR, SNHG19, ELFN1-AS1, LINC00487, and LINC00877) were tested and validated to establish an lncRNA-regulating epigenetic event signature (ELncSig). ELncSig, which was established based on independent lymphoma datasets, could distinguish different survival outcomes. Functional characterization of ELncSig showed that it could be an indicator of the immune microenvironment and is correlated with distinctive mutational characteristics. Univariate and multivariate analyses showed that ELncSig was independent of traditional prognostic factors. The novel immune-related ELncSig exhibits promising clinical prognostic value for DLBCL.

Clinically approved combination immunotherapy: Current status, limitations, and future perspective.

Immune-checkpoint inhibitor-based combination immunotherapy has become a first-line treatment for several major types of cancer including hepatocellular carcinoma (HCC), renal cell carcinoma, lung cancer, cervical cancer, and gastric cancer. Combination immunotherapy counters several immunosuppressive elements in the tumor microenvironment and activates multiple steps of the cancer-immunity cycle. The anti-PD-L1 antibody, atezolizumab, plus the anti-vascular endothelial growth factor antibody, bevacizumab, represents a promising class of combination immunotherapy. This combination has produced unprecedented clinical efficacy in unresectable HCC and become a landmark in HCC therapy. Advanced HCC patients treated with atezolizumab plus bevacizumab demonstrated impressive improvements in multiple clinical endpoints including overall survival, progress-free survival, objective response rate, and patient-reported quality of life when compared to current first-line treatment with sorafenib. However, atezolizumab plus bevacizumab first-line therapy has limitations. First, cancer patients falling into the criteria for the combination therapy may need to be further selected to reap benefits while avoiding some potential pitfalls. Second, the treatment regimen of atezolizumab plus bevacizumab at a fixed dose may require adjustment for optimal normalization of the tumor microenvironment to obtain maximum efficacy and reduce adverse events. Third, utilization of predictive biomarkers is urgently needed to guide the entire treatment process. Here we review the current status of clinically approved combination immunotherapies and the underlying immune mechanisms. We further provide a perspective analysis of the limitations for combination immunotherapies and potential approaches to overcome the limitations.

ALKBH5 Facilitates Hypoxia-Induced Paraspeckle Assembly and IL8 Secretion to Generate an Immunosuppressive Tumor Microenvironment.

The dynamic changes of RNA N6-methyl-adenosine (m6A) during cancer progression contribute to quick adaption to microenvironmental changes. Here, we profiled the cancer cell m6A dynamics in the hypoxic tumor niche and its pathological consequences in glioblastoma multiforme (GBM). The m6A demethylase ALKBH5 was induced in GBM models under hypoxic conditions and was associated with a hypoxic gene signature in GBM patient samples. Depletion or inactivation of ALKBH5 in GBM cells significantly suppressed hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in allograft tumors. Expression and secretion of CXCL8/IL8 were significantly suppressed in ALKBH5-deficient tumors. However, ALKBH5 did not regulate CXCL8 m6A directly. Instead, hypoxia-induced ALKBH5 erased m6A deposition from the lncRNA NEAT1, stabilizing the transcript and facilitating NEAT1-mediated paraspeckle assembly, which led to relocation of the transcriptional repressor SFPQ from the CXCL8 promoter to paraspeckles and, ultimately, upregulation of CXCL8/IL8 expression. Accordingly, ectopic expression of CXCL8 in ALKBH5-deficient GBM cells partially restored TAM recruitment and tumor progression. Together, this study links hypoxia-induced epitranscriptomic changes to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. SIGNIFICANCE: Hypoxia induces tumor immune microenvironment remodeling through an ALKBH5-mediated epigenetic and epitranscriptomic mechanism, providing potential immunotherapeutic strategies for treating glioblastoma.