Computational prediction of MHC anchor locations guides neoantigen identification and prioritization.

Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen identification and prioritization relies on correctly predicting whether the presenting peptide sequence can successfully induce an immune response. Because most somatic mutations are single-nucleotide variants, changes between wild-type and mutated peptides are typically subtle and require cautious interpretation. A potentially underappreciated variable in neoantigen prediction pipelines is the mutation position within the peptide relative to its anchor positions for the patient's specific MHC molecules. Whereas a subset of peptide positions are presented to the T cell receptor for recognition, others are responsible for anchoring to the MHC, making these positional considerations critical for predicting T cell responses. We computationally predicted anchor positions for different peptide lengths for 328 common HLA alleles and identified unique anchoring patterns among them. Analysis of 923 tumor samples shows that 6 to 38% of neoantigen candidates are potentially misclassified and can be rescued using allele-specific knowledge of anchor positions. A subset of anchor results were orthogonally validated using protein crystallography structures. Representative anchor trends were experimentally validated using peptide-MHC stability assays and competition binding assays. By incorporating our anchor prediction results into neoantigen prediction pipelines, we hope to formalize, streamline, and improve the identification process for relevant clinical studies.

High glucose: an emerging association between diabetes mellitus and cancer progression.

The association of cancer and diabetes mellitus (DM) has been studied for decades. Hyperglycemia and the imbalance of hormones are factors that contribute to the molecular link between DM and carcinogenesis and cancer progression. Hyperglycemia alone or in combination with hyperinsulinemia are key factors that promote cancer aggressiveness. Many preclinical studies suggest that high glucose induces abnormal energy metabolism and aggressive cancer via several mechanisms. As evidenced by clinical studies, hyperglycemia is associated with poor clinical outcomes in patients who have comorbid DM. The prognoses of cancer patients with DM are improved when their plasma glucose levels are controlled. This suggests that high glucose level maybe be involved in the molecular mechanism that causes the link between DM and cancer and may also be useful for prognosis of cancer progression. This review comprehensively summarizes the evidence from recent pre-clinical and clinical studies of the impact of hyperglycemia on cancer advancement as well as the underlying molecular mechanism for this impact. Awareness among clinicians of the association between hyperglycemia or DM and cancer progression may improve cancer treatment outcome in patients who have DM.

Neoantigen vaccine platforms in clinical development: understanding the future of personalized immunotherapy.

INTRODUCTION: Derived from genetic alterations, cancer neoantigens are proteins with novel amino acid sequences that can be recognized by the immune system. Recent evidence demonstrates that cancer neoantigens represent important targets of cancer immunotherapy. The goal of cancer neoantigen vaccines is to induce neoantigen-specific immune responses and antitumor immunity, while minimizing the potential for autoimmune toxicity. Advances in sequencing technologies, neoantigen prediction ?algorithms,? and other technologies have dramatically improved the ability to identify and prioritize cancer neoantigens. These advances have generated considerable enthusiasm for ?the ?development of neoantigen vaccines. Several neoantigen vaccine platforms are currently being evaluated in early phase clinical trials including the synthetic long peptide (SLP), RNA, dendritic cell (DC), and DNA vaccine platforms. AREAS COVERED: In this review, we describe, evaluate the mechanism(s) of action, compare the advantages and disadvantages, and summarize early clinical experience with each vaccine platform. We provide perspectives on the future directions of the neoantigen vaccine field. All data are derived from PubMed and ClinicalTrials search updated in October 2020. EXPERT OPINION: Although the initial clinical experience is promising, significant challenges to the success of neoantigen vaccines include limitations in neoantigen identification and the need to successfully target the immunosuppressive tumor microenvironment.

Selective Cytotoxicity of Kaempferia parviflora Extracts in Human Cell Lines.

OBJECTIVE: Aims of this study were to (1) compare anti-proliferative activity between aqueous and ethanol Kaempferia parviflora (KP) extracts in both cancer (Human urinary bladder cancer cell, T24) and normal cell lines (Human umbilical vein endothelial cell, HUVEC). (2) confirm selective cytotoxicity of ethanol KP extract to normal and different cancer cell lines (3) investigate its cellular mechanism through p53 and SIRT1 gene expression. METHODS: Phytochemical difference between aqueous and ethanol extract was determined by thin layer chromatography (TLC). Screening for cytotoxic activity in human cell lines was performed by cell viability assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent. P53 and SIRT1 gene expression were quantified using RT-PCR. RESULTS: Results from the cell viability assay were shown as follows: (1) ethanol extract possessed higher toxicity to cancerous cells than aqueous extract (2) ethanol extract exhibited higher cytotoxicity to cancerous cells than normal cells (3) ethanol extract also showed cytotoxicity, with different levels, to three prostate cancer cell lines varying in aggressiveness. (4) ethanol KP extract induced cell death in T24 via p53 gene expression and prolonged cell survival in HUVEC through SIRT1 gene expression. CONCLUSION: These findings implied that ethanol KP extract might possibly be an alternative for cancer adjuvant therapy through the mechanism of selective p53 and SIRT1 gene expression.

NF-κB and STAT3 co-operation enhances high glucose induced aggressiveness of cholangiocarcinoma cells.

AIMS: The present report aimed to investigate the underlying genes and pathways of high glucose driving cholangiocarcinoma (CCA) aggressiveness. MAIN METHODS: We screened and compared the gene expression profiles obtained by RNA sequencing, of CCA cells cultured in high and normal glucose. Results from the transcriptomic analysis were confirmed in additional cell lines using in vitro migration-invasion assay, Western blotting and immunocytofluorescence. KEY FINDINGS: Data indicated that high glucose increased the expression of interleukin-1ß (IL-1ß), an upstream regulator of nuclear factor-κB (NF-κB) pathway, through the nuclear localization of NF-κB. High glucose-induced NF-κB increased the migration and invasion of CCA cells and the expression of downstream NF-κB targeted genes associated with aggressiveness, including interleukin-6, a potent triggering signal of the signal transducer and activator of transcription 3 (STAT3) pathway. Such effects were reversed by inhibiting NF-κB nuclear translocation which additionally reduced the phosphorylation of STAT3 at Y705. SIGNIFICANCE: These results indicate that NF-κB is activated by high glucose and they suggest that NF-κB interaction with STAT3 enhances CCA aggressiveness. Therefore, targeting multiple pathways such as STAT3 and NF-κB might improve CCA treatment outcome especially in condition such as hyperglycemia.

Recent developments in neoantigen-based cancer vaccines.

Cynics point out that a cure for cancer has been "around the corner" for the last 50 years. Nevertheless, the recent convergence of deep DNA, RNA, and proteomic technologies with enhanced understanding of the nuances of the adaptive immune system has generated great optimism amongst researchers. The extraordinary heterogeneity of various cancers, once thought to be a major therapeutic hurdle, may now be bypassed via "personalized" vaccine treatments. Specifically, these treatments involve the identification of MHC-bound peptides that are unique to a patient's cancer (neoantigens), followed by immunization with peptides, RNA, or DNA that encodes these neoantigens via various delivery systems, thus amplifying the immune system's response to the particular cancer. Such approaches have shown dramatic results in animal studies. Not surprisingly, then, the field of neoantigen-based immunotherapy has advanced at a spectacular rate, necessitating that interested individuals stay apprised of recent developments. Following an introduction to the subject, we thus focus on aspects that are particularly fast-moving; the cellular sources of neoantigens, which are surprisingly diverse, the tools that are used for their identification, and the status of the numerous clinical trials that are now being conducted.