James Arnold, DPhil, Wade F. B. Thompson CLIP Investigator King's College London Area of Research: All Cancers, Cáncer de mama Immune suppression within the tumor is a major hurdle to preventing the patient’s immune system from attacking and eradicating malignant cells. Dr. Arnold’s team has demonstrated that the enzyme heme oxygenase-1 (HO-1) can be pivotal to maintaining efficient immune suppression in the tumor microenvironment. HO-1 degrades heme to generate the biologically active by-products; biliverdin, ferrous iron and carbon monoxide, the last of which has been demonstrated to be immune suppressive. In addition to finding that HO-1 is expressed by a subset of tumor associated macrophages in a variety of preclinical models, they demonstrated that pharmacological inhibition using a clinically relevant small molecule inhibitor of HO-1, or genetic inactivation of the gene within the myeloid compartment, can potentiate an antitumor immune response elicited by chemotherapy to allow immunological control of tumor growth. Different chemotherapies can stimulate the immune response against cancer through a variety of seemingly discrete mechanisms, but the biological ‘rules’ to predict these responses are lacking, and how they synergize with HO-1 inhibition has never previously been studied. Using a spontaneous murine model of breast cancer, Dr. Arnold is studying how different chemotherapies promotes anti-tumor immune responses and their synergy with HO-1 inhibition to deliver efficient immunological control of tumor growth. He will immune-profile the stromal compartment from the tumor using cutting-edge single cell RNA-sequencing to assess immunological heterogeneity and changes with treatment. The current project will probe mechanism and solidify the optimal chemotherapy pairing for HO-1 inhibition, as well as identify novel biomarkers, to facilitate routes to clinical translation for this novel immunotherapy approach. Projects and Grants Harnessing the immunological response elicited by chemotherapy to facilitate the immunotherapy treatment of cancer King’s College London | All Cancers, Breast Cancer | 2021
