Background: Solid tumours generate an immunosuppressive tumour immune microenvironment (TIME) which hinders or abrogates many types of therapeutics, particularly immunotherapies. Targeted radiotherapy may potentiate long-term anti-tumour effects through reinstating an inflammatory environment in previously immunologically cold tumours, but the mechanisms behind this are poorly understood and have not been exploited for combination with immunotherapy.
Aims: We aim to examine the molecular and cellular changes to the tumour microenvironment after targeted radiotherapy in PDX models of castrate-resistant prostate cancer.
Methods: We treated six prostate-derived xenografts (PDX) from patients with metastatic castrate-resistant prostate cancer with the targeted radioligand 177Lutetium-PSMA. We measured tumour growth over 14 days, and analysed changes to the tumour tissue at harvest with flow cytometry, RNAseq, and immunohistochemistry.
Results: After treatment with radiotherapy, we found in the tumour increases in markers of mature and activated endothelium, and increased infiltration of immune cells and activated subsets. We also found higher expression of the extrinsic apoptotic marker Fas, and intrinsic apoptotic marker cleaved caspase 3 in tumour cells. Tumour size decreased, and correlated with the amount of target-antigen expression.
Conclusion: These initial data show there are changes occurring in the TIME after radiotherapy that relate to increased immune access, activation, and recognition of the tumour. This creates a better landscape for further treatment with immunotherapies, particularly adoptive cell therapies which normally struggle to surmount the microenvironment. Further investigation will examine immune subset functionality, microenvironmental cytokines, and combination treatment with adoptive T-cell therapy.