SLIDE 1
Levels of Cytotoxic T-cell infiltration is Important for Patient Survival in Ovarian Cancer
Zhang et al. N Engl J Med (2004)
Re-activating Anti-tumour Immunity in Ovarian Cancer using - - PowerPoint PPT Presentation
Re-activating Anti-tumour Immunity in Ovarian Cancer using - - PowerPoint PPT Presentation
Radical treatments for gynaecological cancers: HOPE or HYPE? Re-activating Anti-tumour Immunity in Ovarian Cancer using Non-coding RNAs Sherry Y. Wu, Ph.D. School of Biomedical Sciences The University of Queensland Levels of Cytotoxic T-cell
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SLIDE 3
Current Strategies to Enhance T-cell Activities in Tumours
- T-cell therapy
– Labour intensive; limited effect
- Immune checkpoint antibodies (αCTLA4/PD-1/PDL1)
– Ovarian cancer
- Only 1/17 patients had an objective response (N Engl J Med 2012)
- αPDL1, 5.8% response rate; αPD1, 15% response rate (Int J Clin
Oncol 2016)
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Prevalence of Somatic Mutations in Different Cancer Types
Alexandrov et al. Nature 2013
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Immune Therapy in Ovarian Cancer
C
- n
t r
- l
a C T L A 4 / P D L 1 0.0 0.5 1.0 1.5
ID8 Ovarian Cancer Model
Study Goal: To develop strategies to sensitize ovarian tumours to immune therapy, thereby reducing the recurrence rate and improving long-term survival.
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Infiltration of Cytotoxic T-cells in Ovarian Cancer
Wu et al. Preliminary Results
Several non-coding RNAs differentially expressed between tumours with high
- vs. low levels of T cells
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Effect of microRNA expression on Infiltration
- f CD8+ T-cells
ID8-Control miR ID8-target miRNA
CD8 staining
SLIDE 8
Effect of microRNA expression on Infiltration of CD8+ T-cells
ID8-Control miR ID8-target miRNA
SLIDE 9
Molecular Mechanism
- Understanding the molecular mechanism of action
could help us identify markers predictive of response
Control miR Target miR Statistical analyses Whole Genome Array (>22,000 genes) ID8 Cells
- PCYOX1
- MGST3
- LGALS3BP
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Effect of MGST3, PCYOX1, and LGALS3BP
- n CD8 T-cell infiltration
SLIDE 11
Effect of MGST3, PCYOX1, and LGALS3BP Expression on Cytokines Important for CTL Function
SLIDE 12
Lgals3bp: Lectin Galactoside-binding Soluble 3 Binding Protein
- Secreted protein; Expressed in nucleus and plasma membrane
- LGALS3BP binds with high affinity to CD33-related Siglecs
(transmembrane lectins expressed on leukocytes) and inhibits neutrophil activation
- E-selectin ligand, predict metastasis and poor survival of ER- breast
cancer
- Activates Akt, JNK, and RAS signaling cascade in cancer cells
- Knockout model phenotype (Lgals3bptm1Megt/Lgals3bptm1Megt)
– Increased circulating interferon-gamma level – Increased circulating IL-12 level (IL-12 plays a central role in T-cell mediated responses in inflammation)
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Conclusions & Future Directions
Conclusions MiRNA treatment significantly increased the level of infiltrating T-cells in tumours and decreased tumour burden. There was a significantly down-regulated immune suppressive pathways in
- varian cancer.
Future Directions Combination therapy with αCTLA4/PDL1
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Acknowledgements
Ovarian Cancer Research Foundation
Contributors
- Mamur Chowdhury
- Janet Fan
- John Hooper
- Maria Kavallaris
- Willem Overwijk
- Anil Sood
- Ray Steptoe
- Michelle Tran
- Teja Veerati
- Dorothy Yang
SLIDE 15
Financial Disclosure
Honoraria/ Expenses Consulting/ Advisory Board Funded Research Royalties/ Patent Stock Options Ownership / Equity Position Employee Other (please specify)
Ovarian Cancer Research Foundation X
March 30 ‐ April 2, 2014 Sheraton Sonoma County Petaluma, California
Off-Label Product Use
Will you be presenting or referencing off‐label or investigational use of a therapeutic product? X No Yes, please specify: No, nothing to disclose X Yes, please specify: