Graduate Student Harvard Medical School Boston, Massachusetts, United States
Introduction/Rationale: Colorectal cancer (CRC) is prevalent and deadly. However, the effectiveness of immune checkpoint blockade immunotherapies remains limited for the majority of CRC patients. Therefore, it is important to study the dynamic and complex CRC tumor microenvironment (TME) in the gastrointestinal tract to achieve better therapeutic results. Tumor innervation is associated with poor prognosis in CRC, yet the mechanistic role of neurons in intestinal tumorigenesis remains poorly understood.
Methods: We extensively use neuronal lineage tracing and chemogenetics to identify the role of intrinsic enteric neuron in CRC growth. We identify the key molecular players in the enteric neuro-immune crosstalk by employing a novel ex vivo coculture system. Finally, we genetically target these molecules in enteric neurons in mice models of CRC and perform single-cell RNA sequencing to dissect the underlying mechanistic pathways.
Results: We reveal extensive innervation in both inflammatory and non-inflammatory CRC models in mice. We demonstrate that intrinsic enteric neurons drive tumor growth. We further show that enteric neurons respond to interferon-γ and directly inhibit CD8+ T cell function in a contact-dependent and -independent manner. Mechanistically, we identify that enteric neurons upregulate an immunosuppressive gene signature characterized by Programmed Cell Death Ligand 1 and the soluble decoy receptor IL-18 binding protein. Disrupting any node in this axis in vivo enhances CD8+ T cell function and significantly reduces intestinal tumor burden. By pharmacologically targeting this axis with a synthetic decoy resistant recombinant IL-18 cytokine, we discover that intestinal tumors normally refractory to checkpoint blockade can be effectively eliminated in mice.
Conclusion: Our study uncovers an enteric neuro-immune circuit that promotes tumorigenesis and introduces a new therapeutic target for colon cancer patients who are unresponsive to current immunotherapies.
