Poster Presentation 28th Lorne Cancer Conference 2016

Induced expression of the immune suppressor Programmed Death Ligand 1 in breast cancer (#120)

Natasha Brockwell 1 2 , Jay Rautela 1 3 , Alex Spurling 1 , Siddartha Deb 4 , Nikola Baschuk 1 , Katie Owen 1 , Hendrika Duivenvoorden 1 , Elgene Lim 2 5 , Belinda Parker 1 2
  1. La Trobe University, Bundoora, VIC, Australia
  2. Olivia Netwon John Cancer Research Institute , Heidelberg, VIC, Australia
  3. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne , VIC, Australia
  4. Walter and Eliza Hall institute , Melbourne, VIC, Australia
  5. Garvan Institute of Medical Research , Sydney , NSW, Australia

Due to limited treatment options, advanced metastatic breast cancer is almost considered incurable. Accumulating evidence suggests that for metastasis to occur, cancer cells must evade host immune surveillance.  One mechanism of immune suppression is tumour cell expression of the checkpoint protein PD-L1. Binding of PD-L1 to its receptor PD-1 located on T cells leads to suppression of the anti-tumour cytotoxic T cell response, allowing tumour cells to escape immune elimination. However, little is known about the expression of PD-L1 throughout metastatic progression or how it is regulated by immune activating cytokines such as type I interferons (IFNs).

Previous work in the breast cancer field has reported that PD-L1 expression in TNBC actually predicts prolonged patient survival, going against the hypothesis the tumour expression of PD-L1 would promote immune suppression and metastatic outgrowth.  We investigated this association in a mouse model of metastasis encompassing cell lines with known metastatic potential. As with the recent human data, results showed that PD-L1 expression inversely correlated with their metastatic potential. Next, we assessed the impact of type I and II IFNs on PD-L1 expression in a variety of human and mouse breast cancer cell lines.  Both type I and II IFN treatment upregulated PD-L1 expression on both human and murine breast cancer cell lines. This suggested a negative feedback loop whereby immune activating cytokines are able to upregulate an immune suppressive ligand. An in vivo experiment was designed to test the effects of combining an immune activating therapy (poly-IC) with an anti-PD-1 antibody. Initial studies show that combining poly-IC and anti-PD-1 therapies leads to a significant reduction in both lung and spine metastasis in a syngeneic mouse model of triple negative breast cancer. Ongoing studies may further highlight the effectiveness of combining immune activing therapies with anti-PD-1/PD-L1 therapies and the relevance of baseline PD-L1 in predicting response to such therapies