Poster Presentation MIN Spring Retreat 2023

Targeted radiotherapy [177Lu]-PSMA-I&T activates the tumour microenvironment for cellular immunotherapy in patient-derived xenograft models of prostate cancer (#104)

Isabel M Everard 1 , Natalie L Lister 1 , Laura H Porter 1 , Shivakumar Keerthikumar 2 3 4 , Renea A Taylor 1 5 , Gail P Risbridger 1 4
  1. Anatomy and Developmental Biology, Monash University, Melbourne, Vic, Australia
  2. Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia
  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic, Australia
  4. Peter MacCallum Cancer Centre, Melbourne, Vic, Australia
  5. Physiology, Biomedicine Discovery Institute, Monash University, Melbourne, Vic, Australia

Background: Solid tumours generate an immunosuppressive tumour microenvironment (TME) which restricts the efficacy of cellular immunotherapeutics, such as chimeric antigen receptor T cells (CAR-T). [177Lu]-PSMA-I&T, a targeted radiotherapy aimed at prostate-specific membrane antigen (PSMA), may potentiate anti-tumour effects through reinstating an inflammatory environment in the tumour. This may involve changes to the vasculature, immune cells, stroma, and tumour epithelial cells. The mechanisms behind this are poorly understood, and could be exploited for combination with CAR-T cells. 

Methods: Eight PDXs from patients with prostate cancer were treated with a single 60MBq dose of targeted radioligand [177Lu]-PSMA-I&T. Tumour growth was measured over 14 days, and changes to the TME were measured at harvest using flow cytometry, RNAseq, and immunohistochemistry. 

Results: Changes in tumour volume were variable between PDXs when treated with targeted radiotherapy, but PDXs expressing the highest levels of PSMA target-antigen showed the most significant growth reduction. RNA sequencing of whole tumour samples post-treatment demonstrated significant differential gene expression in tumours that responded to targeted radiotherapy, including upregulation of inflammatory cytokine pathways. Flow cytometric analysis of the TME demonstrated increased expression of markers associated with mature and activated endothelium, as well as increased infiltration of activated immune subsets and macrophages with M1 polarisation. Tumour cells also upregulated the extrinsic apoptotic marker FAS – a cell death pathway initiated in tumour cells by immune cell interaction.

Conclusion: Initial data demonstrated multiple phenotypic changes in the TME after [177Lu]-PSMA-I&T radiotherapy that mimic an inflammatory response, and could potentiate increased immune access, activation, and recognition of the tumour. Activation of the TME by targeted radiotherapy offers a promising treatment combination with cellular immunotherapy, which normally fails to show efficacy in vivo as a single agent.