Transcription Elongation Factor A (SII) -Like (TCEAL) Gene Family Member-TCEAL2: A Novel Prognostic Marker in Pan-Cancer

Background: Cancer is the leading cause of death in the world. The mechanism is not fully elucidated and the therapeutic effect is also unsatisfactory. In our study, we aim to find new target gene in pan-cancer.Methods: Differentially expressed genes (DEGs) was screened out in various types of cancers from GEO database. The expression of DEG (TCEAL2) in tumor cell lines, normal tissues and tumor tissues was calculated. Then the clinical characteristics, DNA methylation, tumor infiltration and gene enrichment of TCEAL2 was studied. Results: TCEAL2 expressions were down-regulated in most cancers. Its expression and methylation were positively or negatively associated with prognosis in different cancers. The tumor infiltration results revealed that TCEAL2 was significantly related with many immune cells especially NK cells and immune-related genes in majority cancers. Furthermore, tau protein and tubulin binding were involved in the molecular function mechanisms of TCEAL2. Conclusion: TCEAL2 may be a novel prognostic marker in different cancers and may affect tumor through immune infiltration.

RESULTS OF THE ANALYSIS OF CLINICAL, MORPHOLOGICAL FACTORS FOR THE PROGNOSIS OF RENAL CELL CARCINOMA

This article analyzes the main clinical, morphological factors affecting the outcome of the disease, and determines their proportion. Favorable clinical and morphological signs were: absence of lymphovascular invasion, lymphocytic infiltration of the tumor, small tumor size, absence of concomitant pathology. Adverse prognosis factors include: lymphovascular invasion, absence of tumor infiltration by lymphocytes, large tumor size and severe concomitant pathologies.

DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.

NI-15 Comparison of amide proton transfer imaging with perfusion imaging of using arterial spin-labeling for evidence of tumor cells in glioma

BACKGROUND: Infiltrative gliomas show cerebral edema and tumor infiltration as areas of hyperintensity in FLAIR image. Amide proton transfer (APT) and cerebral blood flow (CBF) are useful for evaluating the tumor invasion. In this study, arterial spin-labeling (ASL)-CBF and APT were compared to determine which method was superior for predicting tumor infiltration in gliomas, pathologically. METHODS: Fifteen specimens from 5 glioma patients with confirmed selective sampling were obtained. Based on APT signal intensity (SI), regions of interests (ROIs) were selected for biopsy. Same regions of these ROIs were marked on the same slice of ASL imaging. Samples were pathologically assessed for cell density and vessel density. APT SI and ASL-CBF were analyzed for each specimen. RESULTS: APT signal intensity (SI) showed a strong correlation with cell density (R = 0.887, P < 0.0001). ASL-CBF showed no correlation with cell density (R = 0.240; P = 0.3836) but a correlation with vessel density (R = 0.697; P = 0.0038). In linear regression analysis, APT SI showed a positive relationship with cell density (R2 = 0.787, P < 0.0001, linear regression; y = 30.70 + 6.24E-3*x). CONCLUSIONS: APT imaging was superior in predicting cellular proliferation than ASL-CBF and a powerful predictor of cell density. APT imaging allowed revelation of novel clues reflecting tumor proliferation in brain tumor; to date, this is the first known report to assess cell density among various brain tumors and conditions after treatment.

ACSL4 Expression Is Associated With CD8+ T Cell Infiltration and Immune Response in Bladder Cancer

ObjectiveThis study aimed to explore the role of ACSL4 in CD8+ T cell tumor infiltration and outcomes of bladder cancer (BLCA) patients after immunotherapy.MethodsThe correlation between ACSL4 expression and tumor infiltration of immune cells was analyzed using the Tumor Immune Estimation Resource database. The prognostic significance of ACSL4 in BLCA was analyzed using Kaplan–Meier curves. Immunohistochemistry was used to detect CD8+ T cell infiltration in tumors with high and low ACSL4 expression obtained from patients at the Fudan University Shanghai Cancer Center. The relationships between immune checkpoint genes and immune response were analyzed using The Cancer Genome Atlas and IMvigor 210 cohorts. The molecular functions, cellular components, and biological processes involving ACSL4 were explored using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment pathway analyses.ResultsThe expression level of ACSL4 was significantly correlated with the infiltration of CD8+ T cells in BLCA tumors (r = 0.192, P = 2.22e-04). Elevated ACSL4 was associated with suppressed tumor progression and better outcomes for BLCA patients. The higher expression level of ACSL4 predicted better immunotherapeutic responses and was associated with higher expression levels of core immune checkpoint genes, including CD274, CTLA4, PDCD1, and LAG3, compared with the low ACSL4 expression group.ConclusionThis study demonstrated for the first time that elevated ACSL4 correlated significantly with CD8+ T cell infiltration and contributed to better immunotherapeutic responses in BLCA patients. Furthermore, ACSL4 serves as a novel biomarker for predicting patient outcomes after immunotherapeutic treatments, which may improve the development of individualized immunotherapy for BLCA.

The Identification of a Tumor Infiltration CD8+ T-Cell Gene Signature That Can Potentially Improve the Prognosis and Prediction of Immunization Responses in Papillary Renal Cell Carcinoma

BackgroundCD8+ T cells, vital effectors pertaining to adaptive immunity, display close relationships to the immunization responses to kill tumor cells. Understanding the effect exerted by tumor infiltration CD8+ T cells in papillary renal cell carcinoma (papRCC) is critical for assessing the prognosis process and responses to immunization therapy in cases with this disease.Materials and ApproachesThe single-cell transcriptome data of papRCC were used for screening CD8+ T-cell-correlated differentially expressed genes to achieve the following investigations. On that basis, a prognosis gene signature associated with tumor infiltration CD8+ T cell was built and verified with The Cancer Genome Atlas data set. Risk scores were determined for papRCC cases and categorized as high- or low-risk groups. The prognosis significance for risk scores was assessed with multiple-variate Cox investigation and Kaplan–Meier survival curves. In addition, the possible capability exhibited by the genetic profiles of cases to assess the response to immunization therapy was further explored.ResultsSix hundred twenty-one cell death-inhibiting RNA genes were screened using single-cell RNA sequencing. A gene signature consisting of seven genes (LYAR, YBX1, PNRC1, TCF25, MYL12B, MINOS1, and LINC01420) was then identified, and this collective was considered to be an independent prognosis indicator that could strongly assess overall survival in papRCC. In addition, the data allowed papRCC cases to fall to cohorts at high and low risks, exhibiting a wide range of clinically related features as well as different CD8+ T-cell immunization infiltration and immunization therapy responses.ConclusionsOur work provides a possible explanation for the limited response of current immunization checkpoint-inhibiting elements for combating papRCC. Furthermore, the researchers built a novel genetic signature that was able to assess the prognosis and immunotherapeutic response of cases. This may also be considered as a promising therapeutic target for the disease.

Comparison of Transplant Donor and Third-Party Donor Derived CMV-Specific T Cells for CMV Infection after Allogenic Stem Cell Transplantation

Background: Cytomegalovirus (CMV) infection is a major and potentially life-threatening complication after allogenic hematopoietic stem cell transplantation (allo-SCT). Adoptive transfer of CMV-specific T cells (CTL) from original transplant donor or third-party donor has both emerged as an effective method for CMV infection after allo-SCT. The potential advantages of third party CTL versus transplant donor CTL includes that it is not limited by donor viral immune and can be banked in advance for clinical use. However, as the expansion and persistent of transfused third-party CTL in vivo was considered to be shorter when compared with donor CTL, can third-party CTL provide comparable long-term antiviral efficacy as transplant donor CTL? In fact, the safety and efficacy of these two kinds of CTL have not been compared directly. In addition, the mechanisms driving sustained antiviral immunity induced by these two kinds of CTL remains to be established and compared. Methods: i) We established humanized CMV-infected mouse model and tumor-infiltration mouse model, and compared the antiviral ability of transplant donor and third-party donor derived CTL for CMV infection in mouse models. We comparatively investigated the in vivo recovery of CMV-specific immunity and analyzed the underlying mechanisms driving sustained antiviral immunity induced by these two types of CTL therapy. ii) We collected data from 31 patients who received third-party CTL and selected matched pairs of 62 patients who received donor CTL for refractory CMV infection after allo-SCT, and compared the safety and efficacy of these two kinds of CTL for CMV infection in clinical patients. We also track the infused CTL populations and evaluated the recovery of virus-specific immunity in clinical patients after donor and third-party CTL therapy. Results: i) In mouse models, we observed that adoptively infused donor and third-party CTL could both migrated to the virus or tumor infiltration organs, and contributed to comparable diminishing in CMV pathology and viral burden in target organs. The kinetics of CMV-specific immunity recovery was comparable in donor and third-party CTL group, which further conferred the comparable antiviral response of these two kinds of CTL for CMV infection. When performed a detailed analysis of the recovered source of CTL, we observed a preferential proliferation and expansion of graft-derived endogenous CTL in both donor and third-party CTL therapy group. ii) In clinical patients, adoptive therapy with donor or third-party CTL had comparable clinical response without significant therapy-related toxicity. The cumulative CR rates at 4 th weeks after CTL infusion was 80.6% in donor group and 83.1% in third-party group. We also observed strong expansion of CD8 + tetramer + T cells both after donor and third-party CTL infusion, which were associated with a reduced or cleared viral load. Conclusion:Adoptive therapy with transplant donor or third-party CTL had comparable antiviral response for CMV infection by promoting the restoration of CMV-specific immunity. Our data suggest that both transplant donor or third-party CTL may stimulate the recovery of graft-derived endogenous CMV-specific immunity. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.