Investigating the anti-tumour effects of anti-PD-L1 immune checkpoint blockade combined with ionising radiation in the TrampC1 prostate cancer model.


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Richard Bryant1,Yiannis Philippou1,Hanna Sjoberg1,Emma Murphy1,Said Alyacoubi1,Keaton Jones1,Alex Gordon-Weeks1,Gillies McKenna1,Uzi Gileadi1,Vincenzo Cerundolo1,Ian Mills1,Freddie Hamdy1,Ruth Muschel1
1University of Oxford

Abstract

Background

Ionising irradiation enhances innate and adaptive anti-tumour immunity. Effects of radiotherapy on anti-tumour immunity could be harnessed through multi-modality therapy. There is a need to improve treatment outcomes for high risk localized and locally advanced prostate cancer, potentially through multi-modality therapy. We investigated the tumour microenvironment immune response of prostate cancer xenografts to radiotherapy in immunocompetent murine pre-clinical models. We then tested whether radiotherapy-induced tumour growth delay could be enhanced with PD-L1 inhibition.

Method

Hypo-fractionated radiotherapy was delivered to TrampC1 prostate cancer subcutaneous flank xenografts. Tumour growth delay was assessed together with flow-cytometry and NanoString analysis of tumour microenvironment immune cells. Tumours were treated with 3x5Gy +/- anti-PD-L1, and tumour growth and immune cell populations were analysed.

Results

3x5Gy irradiation resulted in a significant tumour growth delay of TrampC1 prostate cancer flank tumour xenografts. Tumour microenvironment changes at 4 and 7 days post-irradiation included increased tumour-infiltrating macrophages and antigen-presenting cells on flow-cytometry, and up-regulation of PD-1/PD-L1, CD8 T-cell, antigen-presenting cell, and regulatory T-cell genes on NanoString immune cell profiling. At tumour regrowth following 3x5Gy the tumour microenvironment had normalised on flow cytometry, however reduced CD8+, natural killer and antigen-presenting cell gene transcripts were demonstrated on NanoString immune profiling. Inhibition of PD-L1 plus 3x5Gy resulted in a trend towards enhanced tumour growth delay versus 3x5Gy alone, but the tumour immune cell microenvironment at 400mm3 end-point was unchanged.

Conclusion

Sub-lethal 3x5Gy hypo-fractionated radiotherapy resulted in a tumour growth delay and up-regulation of PD-L1, and an initial increase in macrophage and antigen-presenting cell infiltrate in the tumour microenvironment of a TrampC1 prostate cancer flank tumour model. However, combining anti-PDL1 with 3x5Gy did not result in a significantly enhanced anti-tumour effect in the conditions tested. This emphasizes that approaches above and beyond combining radiotherapy and anti-PDL1 are necessary to treat aggressive prostate cancer.