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)

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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