Sir Peter MacCallum Department of Oncology - Theses
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ItemDefining the immune landscape in rectal cancer and its relationship to neo-adjuvant chemoradiotherapy and immunotherapy responses( 2023-07)Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Approximately 25% of these tumours are in the rectum. Rectal cancers that are locally advanced or have poor prognostic features on staging are typically treated with neo-adjuvant chemoradiotherapy prior to surgical resection. However, despite intensive efforts to improve the response rates to neo-adjuvant therapy, most patients do not achieve a complete pathological response. Patients that do achieve a complete response to neo-adjuvant therapy may be candidates for organ preservation. There has been limited progress in identifying treatment protocols with improved therapeutic efficiency, or in extending the treatment options for patients that have an incomplete response. Additional complexity is added by the inability to accurately identify which patients will respond to treatment, and deficiencies in understanding the mechanisms that drive treatment response. This thesis focuses on first reviewing the novel treatment options that have been investigated for patients with rectal cancer to date and assessing the ongoing inclination of surgeons to pursue novel therapies for their patients. Additionally personalised tumour models (tumouroids) and differentially expressed genes were assessed for the utility in predicting which patients are likely to respond to neo-adjuvant therapy. There has been recent attention on the ability of immune checkpoint blockade inhibitors to “rescue” cytotoxic mediated immune responses and extend treatment responses for patients with tumours including melanoma, non-small cell lung carcinoma and renal cell carcinoma. The use of these agents in the setting of neo-adjuvant therapy for rectal cancer remains undefined. Thus, a phase II clinical trial was established to assess the role of immune checkpoint blockade inhibition in the neo-adjuvant setting for rectal cancer, with a particular focus on the effect of this therapy on tumour response and the tumour immune landscape. Finally, the tumour microenvironment has an accepted and essential role in response to neo-adjuvant therapy. However, newly identified cells and cellular structures such as tissue resident memory cells and tertiary lymphoid structures are altering our understanding of anti-tumour immunity but remain under investigated in the setting of rectal cancer. To address this deficiency multiplex immunohistochemistry was employed to define the immune landscape of patients receiving both chemoradiotherapy and immune checkpoint blockade inhibition, with a particular focus on cell types previously under appreciated. Defining the immune landscape of these tumours in such a manner may allow a deeper understanding of the mechanisms driving therapy response and facilitate targeted patient therapy.