Poster Presentation 29th Lorne Cancer Conference 2017

Induction and therapeutic targeting of the PD-1/PD-L1 axis in breast cancer (#131)

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

Due to limited treatment options, advanced metastatic breast cancer is frequently associated with poor survival. For metastasis to occur, cancer cells must evade host immune surveillance and one proposed mechanism is via the up regulation of immune checkpoint proteins in tumour cells, such as 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 changes in PD-L1 expression throughout metastatic progression and/or its regulation by chemotherapy or immune activating cytokines such as interferons (IFNs). Using flow cytometry analysis of PD-L1 cell surface expression, we showed that its expression was highest in the triple negative (TN) subtype and inversely correlated with metastatic progression in a syngeneic mouse model. PD-L1 expression was increased upon tumour cell treatment with the chemotherapeutic doxorubicin and this was enhanced by treatment with IFNs and IFN stimulating agents both in vitro and in vivo. This suggested a negative feedback loop whereby immune stimulating agents lead to secondary dampening of immune activation via up regulation of PD-L1 on the surface of tumour cells. To test if combining immune activation and checkpoint blockade had potential as an anti-metastatic therapeutic, syngeneic mouse models of TN breast cancer were treated with the type I IFN inducer, poly(I:C) alone or in combination with anti-PD-1 antibody. These studies showed that the combination therapy was able to increase T-cell and natural killer (NK) cell activation in circulation and infiltrating the primary tumour. Importantly, combination therapy significantly decreased primary tumour weight and metastatic burden whilst prolonging overall survival compared to single agents alone. Combination strategies incorporating doxorubicin are now being tested. Considering TNBC patients often rely on chemotherapy, this project aims to test the impact of immunotherapies in prolonging survival, including assessment of whether an increase in PD-L1 primary tumour expression post therapy predicts those patients that may benefit from anti-PD1 therapeutics.