Immuno andEpigenetic Therapies
Xiaole Shirley Liu
STAT115, STAT215, BIO298, BIST520
Cancer Immunology• Would tumor grow in another individual?
Effector Lympocytes
• Lymphocytes express highly specific ANTIGEN RECEPTORS on their surface
• Lymphocytes are highly specific for a given structural motif
• Usually CD8+ cells which kill target cells by recognizing foreign peptide-MHC molecules on the target cell membrane.
Tumors
• Cancer cells must express antigen (foreign particles) recognizable and accessible to the immune system -- antigenicity
• The immune system must in turn be able to mount a response against cells bearing such antigens
• Tumors possess a varying degree of immune “Antigenicity” that is unique to each tumor and thus be rejected by immunocompetent hosts.
Cytokines
• Low molecular weight protein mediators involved in cell growth, inflammation, immunity, differentiation and repair
• Production triggered by presence of foreign particles
• Interleukins (ex. IL-2) and interferons• Acts as a potent immunomodulator and
antitumor element, but might have extensive multiorgan toxicity
Active Immonotherapy
• High dose IL-2 (FDA approved for kidney cancer and melanoma)
• Boost overall immune cells inside the patient body
Using Antibodies to Boost Immune Systems
• Anti CTLA-4 and anti-PD1 antibodies can allow T-cell activation, boost immune to kill tumor
Adoptive Immunotherapy
• Isolate tumor-infiltrating lymphocytes (TILs)• Expand their number artificially in cell culture• Infuse TIL back into the bloodstream, recognize
and destroy the tumor cells
CAR• Chimeric antigen receptors: proteins that allow
the T cells to recognize specific antigen on tumors• Side effects: rapid and massive release of
cytokines into the bloodstream
• Find mutations from exome sequencing• Use bioinformatics program to find mutations
that might be immunogenic• Create vectors expressing the small peptides
containing the mutations• Co-culture to activate TIL
Personalized ImmunoTherapy
• Great for melanoma, lung and colon cancer• Immunotherapy specific to each patients’ tumor
mutations
Bioinformatics?
• Which mutations are expressed?• Which peptides are immunogenetic?• Cancer vaccine?
Epigenetic Drugs
• HDAC inhibitor to delay drug resistance
• Minimum 5-aza (DNA demethylation)
13
Treat Cell Lines
Directly Treating Mice
Effect of 5-aza
• Minimum dosage and toxicity, well tolerated• Activate suppressed immune genes• Can use DNA methylation status at these immune
genes to predict patient response• Small % of patients directly cured.• Others re-sensitized for chemotherapy• Can be used with other drugs?
Targeted Epigenetic Drug
• DOT1L inhibitor for MLL Leukemia
Meyer et al, Nat 2013
Targeted Epigenetic Drug
• JQ1 as a BET domain inhibitor, also works on MLL leukemia
Targeted Epigenetic Drug
• EZH2 inhibitors
• Diffuse large B-cell lymphoma
• Hormone independent prostate cancer
• Rhabdoid tumor with SNF5 mutation
Martinez-Garcia & Licht, Nat Genetics 2010
Summary
• Immunotherapy: a living drug!• Active vs adoptive immunotherapy• Personalized immunotherapy: bioinformatics?• Epigenetic therapy: 5-aza immune response• Targeted epigenetic therapy: DOT1L, EZH2,
BRD4
Final Review
• Programming: python and R• Statistics: – Tukey bi-weight, median polish, qnorm
– Hierarchical models, FDR, KS test
– K-means and hierarchical clustering
– PCA, SVM
– HMM
– EM, Gibbs
– LASSO and logistic regression
– Survival analysis
Final Review
• Binformatics: – Microarrays (RMA, LIMMA)
– Ontology and pathway (DAVID, GSEA)
– Batch removal (COMBAT, SVA)
– NGS for DNA-seq (FastQC, Bowtie, BWA, STAR)
– RNA-seq (Cufflinks, DESeq)
– ChIP/DNase-seq (MACS, BETA)
– GWAS (plink, GRAIL)
– Genome-resequencing (GATK)
– Web resources: GEO, UCSC, CBioPortal
Final Review
• Biological problems– Transcriptome and epigenetic profiling
– Transcriptional regulation and TFs
– Epigenetics and chromatin
– Linkage disequilibrium and disease susceptibility
– Tumor sequencing and personalized medicine
– High throughput screening
Acknowledgement
• Chris Cunningham & Asad Usman• Yang Li, Stephanie Chan• Yushu Pang• Taiwen Li, Yue Kang• Shenglin Mei, Bo Li, Peng Jiang