Pan-cancer analysis identifies CD300 molecules as potential immune regulators and promising therapeutic targets in acute myeloid leukemia.

BACKGROUND: CD300s are a group of proteins playing vital roles in immune responses. However, much is yet to be elucidated regarding the expression patterns and clinical significances of CD300s in cancers. METHODS: In this study, we comprehensively investigated CD300s in a pan-cancer manner using multi-omic data from The Cancer Genome Atlas. We also studied the relationship between CD300s and the immune landscape of AML. RESULTS: We found that CD300A-CD300LF were generally overexpressed in tumors (especially AML), whereas CD300LG was more often downregulated. In AML, transactivation of CD300A was not mediated by genetic alterations but by histone modification. Survival analyses revealed that high CD300A-CD300LF expression predicted poor outcome in AML patients; the prognostic value of CD300A was validated in seven independent datasets and a meta dataset including 1115 AML patients. Furthermore, we demonstrated that CD300A expression could add prognostic value in refining existing risk models in AML. Importantly, CD300A-CD300LF expression was closely associated with T-cell dysfunction score and could predict response to AML immunotherapy. Also, CD300A was found to be positively associated with HLA genes and critical immune checkpoints in AML, such as VISTA, CD86, CD200R1, Tim-3, and the LILRB family genes. CONCLUSIONS: Our study demonstrated CD300s as potential prognostic biomarker and an ideal immunotherapy target in AML, which warrants future functional and clinical studies.

Whole-Genome DNA Methylation Sequencing Reveals Epigenetic Changes in Myelodysplastic Syndromes.

Epigenetic dysregulation of cancer-associated genes has been identified to contribute to the pathogenesis of myelodysplastic syndromes (MDS). However, few studies have elucidated the whole-genome DNA methylation in the initiation pathogenesis of MDS. Reduced representation bisulfite sequencing was performed in five de novo MDS patients and four controls to investigate epigenetic alterations in MDS pathogenesis. The mean global methylation in five MDS patients showed no significant difference compared with the four controls. In depth, a total of 1,459 differentially methylated fragments, including 759 hypermethylated and 700 hypomethylated fragments, were identified between MDS patients and controls. Targeted bisulfite sequencing further identified that hypermethylation of DLEU7, FOXR1, LEP, and PANX2 were frequent events in an additional cohort of MDS patients. Subsequently, LEP hypermethylation was confirmed by real-time quantitative methylation-specific PCR in an expanded cohort of larger MDS patients. In clinics, LEP hypermethylation tended to be associated with lower bone marrow blasts and was significantly correlated with U2AF1 mutation. Survival analysis indicated that LEP hypermethylation was associated with a markedly longer survival time but was not an independent prognostic biomarker in MDS patients. Functional studies revealed pro-proliferative and anti-apoptotic effects of leptin in the MDS cell line SKM-1, and it was significantly associated with cell growth and death as well as the Toll-like receptor and NF-kappa B signaling pathways. Collectively, our findings demonstrated that whole-genome DNA methylation analysis identified novel epigenetic alterations such as DLEU7, FOXR1, LEP, and PANX2 methylations as frequent events in MDS. Moreover, LEP might play a role in MDS pathogenesis, and LEP hypermethylation was associated with longer survival but not as an independent prognostic biomarker in MDS.

Pan-cancer analysis reveals distinct clinical, genomic, and immunological features of the LILRB immune checkpoint family in acute myeloid leukemia.

Leukocyte immunoglobulin (Ig)-like receptor Bs (LILRBs), a family of type I transmembrane glycoproteins, are known to inhibit immune activation. Here, we comprehensively evaluated the molecular, prognostic, and immunological characteristics of LILRB members in a broad spectrum of cancer types, focusing on their roles in acute myeloid leukemia (AML). We showed that LILRBs were significantly dysregulated in a number of cancers and were associated with immune-inhibitory phenotypes. Clinically, high expression of LILRB1-LILRB4 predicted poor survival in six independent AML cohorts. Genetically, LILRB1 was associated with more mutational events than other LILRB members, and multiple genes involved in immune activation were deleted in LILRB1 high patients. Epigenetically, LILRB4 was significantly hypomethylated and marked by MLL-associated histone modifications in AML. Immunologically, LILRBs were positively associated with monocytic cells, including M2 macrophages, but were negatively associated with tumor-suppressive CD8 T cells. Importantly, patients with higher LILRB expression generally showed a better response to immune checkpoint blockade (ICB) in five independent immunotherapy cohorts. Our findings reveal critical immunological and clinical implications of LILRBs in AML and indicate that LILRBs may represent promising targets for immunotherapy of AML.

Simultaneous transcatheter arterial chemoembolization and portal vein embolization for patients with large hepatocellular carcinoma before major hepatectomy.

BACKGROUND: Sequential transarterial chemoembolization (TACE) and portal vein embolization (PVE) are associated with long time interval that can allow tumor growth and nullify treatments' benefits. AIM: To evaluate the effect of simultaneous TACE and PVE for patients with large hepatocellular carcinoma (HCC) prior to elective major hepatectomy. METHODS: Fifty-one patients with large HCC who underwent PVE combined with or without TACE prior to hepatectomy were included in this study, with 13 patients in the simultaneous TACE + PVE group, 17 patients in the sequential TACE + PVE group, and 21 patients in the PVE-only group. The outcomes of the procedures were compared and analyzed. RESULTS: All patients underwent embolization. The mean interval from embolization to surgery, the kinetic growth rate of the future liver remnant (FLR), the degree of tumor size reduction, and complete tumor necrosis were significantly better in the simultaneous TACE + PVE group than in the other groups. Although the patients in the simultaneous TACE + PVE group had a higher transaminase levels after PVE and TACE, they recovered to comparable levels with the other two groups before surgery. The intraoperative course and the complication and mortality rates were similar among the three groups. The overall survival and disease-free survival were higher in the simultaneous TACE + PVE group than in the other two groups. CONCLUSION: Simultaneous TACE and PVE is a safe and effective approach to increase FLR volume for patients with large HCC before major hepatectomy.