Improving immunotherapy responses in gastrointestinal cancers

Abstract

Immunotherapy has changed the way we treat patients with varying cancer types. Despite these advances, a large proportion of patients does not respond to treatment. In colon cancer, immunotherapy was first found to be effective in the small group of patients with mismatch repair deficient colon cancers that had spread (metastasised). However, in the large group of patients with metastatic mismatch repair (MMR) proficient colon cancer the immunotherapy is ineffective. In this thesis, I describe the effects of immunotherapy in an earlier stage of disease. We found that 100% of patients with dMMR tumors and 27% of patients with pMMR tumors respond to treatment, with varying types of response and changes in the tumor milieu. Not only the biological differences between dMMR and pMMR tumors are described, but also how these differences can affect the interpretation of imaging such as CT-scans. These findings are important for future trials to properly select patients based on the stage of the disease. In addition, we show how the different types of immune cells (eosinophils, γδ T cells) may be involved in these effects. The importance of medications that can alter the effects of immunotherapy are also highlighted, showing decreased efficacy of immunotherapy in patients receiving antibiotics and/or proton pump inhibitors prior to start or during treatment.