Exploiting lipid-laden macrophages to overcome resistance to cancer immunotherapy
Immune checkpoint blockade (ICB) has revolutionized cancer care yet is ineffective in most patients. Predicting which patients will respond to ICB and how to enhance efficacy are major challenges. ICB efficacy is dependent on the presence of functional T cells in tumors, which are impacted by macrophages. We have discovered that lipid-laden macrophages (LLM) infiltrate tumors to promote cancer progression in association with immune evasion and poor ICB response. Moreover, intratumoral LLMs are elevated in response to overnutrition via dietary fat. How LLMs accumulate lipids to impact ICB and whether they are predictive of ICB efficacy remain unexplored. Our objective is to determine how LLMs limit ICB and how this can be controlled via diet. We hypothesize that LLM predict poor ICB response and that targeting LLM will enhance ICB efficacy. Our goals are to determine (1) the utility of LLM in predicting ICB efficacy and T cell dysfunction in patients; (2) the origin and functional role of LLM in immunosuppression, haematopoiesis and ICB resistance; & (3) how LLM and ICB are impacted by diet and obesity. To establish causality, we will focus on tumors in close proximity to lipid-rich adipose tissue, such as ovarian (OC), prostate (PCa) and breast cancer (BC), which have high LLM and respond poorly to ICB. We will explore the link between LLM and ICB efficacy in patients using samples from a prospective Phase II clinical trial (OC) and human tumor biobank (OC, PCa, BC). In preclinical models, we will use state-of-the-art fate-mapping tools, imaging techniques and spatially-resolved single cell technologies to dissect the interplay between LLM & T cells following ICB and overnutrition. Our work will provide insight into the rewiring of tumor-supportive and immunosuppressive programs in LLM and how diet influences these processes. Weight is an intersectional determinant of health inequities and leveraging diet to improve ICB efficacy may reduce cancer health disparities.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.