Targeting immune suppression to improve the Post-surgical outcome of solid malignancies

Tumour debulking surgery aims to produce a smaller target for adjuvant therapy whilst also removing much of the tumour associated immunosuppression. Even so, cures are rarely seen in either animal studies or human patients receiving debulking surgery plus adjuvant chemo-immunotherapy, despite evidence of effector T cell activation that should be strong enough to overcome tumour growth. Adjuvant immunotherapies can be used to eradicate distant micro metastases or cancer cells that remain after surgery, but have limited success. This could be due to ‘immune brakes’ that continue to operate, suppressing the anti-tumour response. This is particularly true for mesothelioma, metastatic melanoma and colorectal cancer, which are the main focus of this project. Tumour-induced immune suppression may be caused by suppressive immune cells such as regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs). Both of these cellular populations suppress the anti-tumour effector T cell responses including the effectiveness of cytolytic CD8+ T cells both systemically and locally. This project will use a combined approach to alleviate immune suppression in combination with debulking surgery through the targeted removal of suppressive Treg and MDSC subsets. This project aimed to improve the response seen with debulking surgery by removing tumour-associated immune suppression. The hypothesis was that removing these ‘brakes’ on the anti-tumour immune response would release a stronger, lasting anti-tumour response elicited by adjuvant immunotherapy after surgical debulking. Thus, the results from this study may direct future clinical trials and potentially allow partial debulking surgery to remain a valid treatment option for these patients, especially if followed with the appropriate immunotherapy regimens.