Therapeutic induction of PD1/PDL1 and the implication of combination treatment strategies for TNBC
Natasha K. Brockwell1, Jay Rautela2,3, Alex Spurling1, Katie Owen1, Nikola Baschuk1, Hendrika Duivenvoorden1, Belinda Parker1
1Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 2Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, 3Walter and Eliza Hall institute, Parkville, Vic
Due to limited treatment options, advanced metastatic breast cancer is frequently associated with poor survival. A proposed mechanism of metastasis is tumour induced immune suppression, including the upregulation of immune checkpoint proteins such as PD-L1. Little is known about changes in PD-L1 expression throughout metastatic progression and/or its regulation by conventional chemotherapeutics or immune activating cytokines such as interferons (IFNs).
Using preclinical models of TNBC, we have discovered that PD-L1 cell surface expression is increased upon tumour cell treatment with the chemotherapeutic doxorubicin and that induction is further enhanced following treatment with type I IFNs and IFN inducers. To test if combining immune activation and checkpoint blockade had potential as an anti-metastatic therapeutic strategy, syngeneic mouse models of TNBC were treated with the type I IFN inducer poly(I:C) alone or in combination with an anti-PD-1 antibody. These studies showed that the combination therapy increased tumour infiltrating and circulating T-cell and natural killer (NK) cell activation. 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.
Together, our data suggest that blocking PD-1 post chemotherapy may increase therapeutic response in patients with TNBC. This project will test the link between immune activation, PD-L1 expression and therapeutic response and investigate markers pre and post-chemotherapy that could aid in predicting patients that could benefit from anti-PD approaches.
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