| Shrnutí: | <p>The ability of external beam radiation (EBRT) to modulate the tumour immune microenvironment is becoming increasingly well understood, leading to the development of combinatorial EBRT and immunotherapeutic combinations to improve patient responses. Despite this, there is very limited understanding of if, and how, the related modality of targeted radionuclide therapy (TRT) can interact with the immune system. Given its similarities with EBRT it seems likely that immune factors may play a role in the response to TRT. However, differences between the two radiotherapeutic modalities may result in some interesting differences that may be exploitable in combination therapies. As such, I sought to assess the impact of TRT on the tumour immune microenvironment, with the ultimate aim of identifying synergistic TRT and immunotherapy combinations.</p>
<p>Here, I have established a TRT targetable, immunocompetent prostate cancer model in our lab, namely PGLS allografts. This enabled evaluation of the immune response to the clinically relevant radiopharmaceutical [177Lu]-PSMA-I&T. Using this model, I was able to show for the first time that [177Lu]PSMA-I&T is capable of inducing changes to the TIME, with a notable reduction in immune cells 72 hours post treatment followed by a return to no-treatment levels by day 12 with a trend towards an increase. Strikingly this initial decline was not observed for EBRT treatment, though a similar increase in immune cells was seen by day 12. I went on to investigate the potential mechanisms involved in this interaction with the immune system, demonstrating that both TRT and EBRT can induce immunogenic cell death in this model. Interestingly, this ability to eliminate tumour growth in a vaccination study was absent in the treatment of established tumours, suggesting other factors in the TIME are limiting the capacity of TRT to induce a functional immune response. Finally, I investigated potential combinations with immunotherapies to eliminate possible barriers. Transcriptional analysis of a large prostate cancer patient cohort demonstrated a strong correlation of TGFβ expression with worse outcomes highlighting this protein as a potential target for combination therapeutics. However, no synergistic effect was observed in in vivo studies. Strikingly, I demonstrate that TRT can cause a remarkable increase in PDL1 expression suggesting that this may be an important mechanism of radioresistance, thus I suggest that combination of TRT with anti-PDL1 and potentially TGFβ could be a valuable avenue to explore. Ultimately, this work provides evidence that the immune response to TRT is a field worthy of persuing and highlights several key areas of interest for further exploration.</p>
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