Phenotypic plasticity and increased tissue infiltration of TREM1+ mono-macrophages following radiotherapy in rectal cancer. [scRNA-Seq]

Our previously reported phase II and phase III trials have demonstrated that short-course radiotherapy (SCRT) combined with neoadjuvant immunochemotherapy (SIC) has led to clinical benefits in locally advanced rectal cancer (LARC). Characterization of the molecular mechanisms underlying responses to SIC may lead to improved treatment strategies. Here, we prospectively collected and applied multi-omic analyses to paired pre- and post-treatment LARC specimens undergoing SIC. The TREM1+ mono-macrophages subsets that display a pro-inflammatory phenotype are identified and correlate with complete response to SIC. Mechanically, ionizing radiation (IR) induces peripheral TREM1+ mono-macrophages expansion in tumors. Following IR, loss of TREM1 in mono-macrophages undermines antitumor immunity by altering mono-macrophages differentiation and inhibiting CD8+ T cell infiltration and activation. The TREM1+ mono-macrophages response may rely on activation of key inflammatory pathways, including NF-κB signaling and Toll-like receptor pathway. Pharmacological inhibition of TREM1 abolishes IR-induced immunoactivation and reduces combined IR and/or anti-PD-1 treatment. Thus, we establish a crucial role of a mono-macrophages state in mediating effective cancer therapy.