ssessment of the immunological modulation following high intensity focused ultrasound treatment of soft tissue sarcoma and renal cell carcinoma

High intensity focused ultrasound (HIFU) is a treatment modality using ultrasound waves to thermally ablate tissues, including tumours. The coagulative necrosis caused has been hypothesised to increase anti-tumour immune response. This thesis investigated ‘immunecold’ sarcoma tumours and ‘immune-hot’ renal cell carcinoma tumours to explore this effect.Within this thesis an in vivo murine fibrosarcoma model was established to investigate local and systemic immune modulation with associated HIFU treatment(Chapter 3). The immune profile of untreated tumour highlighted a high proportion of CD4 T cells to be Tregs compared to the other tissues. In the first HIFU study a significant increase in the CD8 Tcm T cell memory population was seen in the dLN 24-hours after treatment. In subsequent studies, the treatment area was reduced due to welfare concerns. This showed that in the dLN there was a significantly increase in neutrophils 24-hours after HIFU therapy. When the treatment included aPD-L1 antibody therapy, there was an aPD-L1 associated significant reduction in the tumour growth 5-days post-treatment.Clinical sarcomas have been reported to have varying immune infiltration based on subtype, which may be of interest in HIFU treatment of these tumours. Transcriptomic profiling of the immune populations within different sarcoma subtypes were assessed in Chapter 4. The transcriptomic profile of undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS) showed that tumours that have been historically reported with ‘high’ immune infiltration (UPS) were characterised by increased antigen presentation and macrophages signature, whereas ‘low’ immune infiltration subtype (LMS), was shown to have high expression of structural genes.Finally, the investigation of the immunological changes associated with HIFU treatment in subtypes of ‘immune hot’renal cell carcinoma was conducted using spatial transcriptomics (Chapter 5). Interestingly, HIFU treatment increased interferon pathway (I and II) expression regardless of subtype and treatment specific macrophage and antigen presentation signatures in clear cell RCC (ccRCC), which in untreated patients, showed lower abundance of these signatures compared to the papillary RCC (pRCC) tumours.