Targeting neutrophils in colorectal cancer

Colorectal cancer (CRC) is the second most common cause of cancer death with an alarming rising incidence among young individuals. While the management of early-stage CRC has improved greatly, the median overall survival for patients with metastatic CRC is 30 months. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced solid cancers, yet for CRC continue to lag behind, with the exception of 4% of patients with microsatellite instability. In contrast, several studies have shown limited to no clinical activity of ICI in microsatellite stable (MSS) CRC. A number of clinical trials with drug combinations have been caried out to convert “immune cold” into “immune hot” tumors. However, the objective response rates were disappointingly low. Thus, novel therapeutic concepts are required to improve outcome in MSS CRC patients.We recently built a large-scale single-cell atlas of the CRC tumor microenvironment (TME) and showed remarkable heterogeneity, representing a major challenge in disease management, since patients with the same tumor subtype can have different immunotherapy responses. Moreover, we identified a subset of neutrophils, the most abundant leukocytes in the blood and highly enriched in the CRC TME, that could fuel ICI response. I propose to fill the knowledge gaps on the neutrophil diversity and function in MSS CRC using cutting-edge single-cell techniques and deep learning methods. We aim to: 1) chart multi-omics single-cell neutrophil map of the bone marrow-tumor axis; 2) identify neutrophil cell niches using samples from an ICI clinical trial and spatial single-cell transcriptomics; 3) relate neutrophil cell niches to clinical correlates using a large biobank and spatial single-cell proteomics; and 4) perform mechanistic studies using patient-derived tumor fragments and mouse models. The knowledge gain will lead to rationale for novel therapeutic framework that exploits anti-tumor strategies of the innate and adaptive immunity.