The role of low dose chemotherapy in sensitising the colon tumour microenvironment to immunotherapy (360G-Wellcome-202426_Z_16_Z)

Metastatic colorectal cancer (CRC) is a lethal disease. Current therapies involve surgery, or palliative chemotherapy, comprising combinations of fluorouracil, oxaliplatin or irinotecan. While therapeutic interventions are beneficial, the overall prognoses for patients with CRC are poor. Therefore, new strategies to treat this problem are needed. Immunotherapies have potential for treatment of metastatic disease as they act through unrelated mechanisms. Recent data has shown that low-dose chemotherapy in combination with immunotherapeutic targeting using monoclonal antibodies can enhance tumour cell elimination by antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC). Using an established syngeneic in vitro model of colon cancer and immune effector assays, the aim of this project will be to investigate the effects of low dose chemotherapy, fluorouracil, 5FU, on overriding colon cancer induced immunosuppressive potential and activating innate effector functions in vitro. Preliminary data indicates that 5FU treatment of CT26 cells in-vitro induces PD-L1 expression on CT26 cells. Additionally, we have evidence that low dose 5FU treatment of CT26 cells induces co-cultured macrophage effector function in tumour cell clearance in vitro. We will investigate in vitro if treatment of CT26, colon cancer cells, with 5FU in the presence of anti-PD-L1 antibody will enhance ADCC/ADCP mediated tumour cell clearance by macrophages.