Arf1 Ablation in Colorectal Cancer Cells Activates a Super Signal Complex in DC to Enhance Anti‐Tumor Immunity

Abstract

The anti‐tumor immune response relies on interactions among tumor cells and immune cells. However, the molecular mechanisms by which tumor cells regulate DCs as well as DCs regulate T cells remain enigmatic. Here, the authors identify a super signaling complex in DCs that mediates the Arf1‐ablation‐induced anti‐tumor immunity. They find that the Arf1‐ablated tumor cells release OxLDL, HMGB1, and genomic DNA, which together bound to a coreceptor complex of CD36/TLR2/TLR6 on DC surface. The complex then is internalized into the Rab7‐marked endosome in DCs, and further joined by components of the NF‐κB, NLRP3 inflammasome and cGAS‐STING triple pathways to form a super signal complex for producing different cytokines, which together promote CD8+ T cell tumor infiltration, cross‐priming and stemness. Blockage of the HMGB1‐gDNA complex or reducing expression in each member of the coreceptors or the cGAS/STING pathway prevents production of the cytokines. Moreover, depletion of the type I IFNs and IL‐1β cytokines abrogate tumor regression in mice bearing the Arf1‐ablated tumor cells. These findings reveal a new molecular mechanism by which dying tumor cells releasing several factors to activate the triple pathways in DC for producing multiple cytokines to simultaneously promote DC activation, T cell infiltration, cross‐priming and stemness.

Host protein ARF1 is a proviral factor for SARS-CoV-2 and a candidate broad-spectrum therapeutic target

“…ARF1 is also implicated in progression and invasiveness of various human cancers, such as non-small cell lung cancer, colorectal cancer, breast cancer, epithelial ovarian cancer, and pancreatic adenocarcinoma, which has attracted great interest in developing ARF1-targeting intervention strategies for oncotherapy 37,38,[74][75][76][77] .…”

“…ARF1 has been suggested as a cellular protein potentially involved in multiple virus infections [31][32][33][34][35] ; however, its role in SARS-CoV-2 infection is unknown. Moreover, the dysregulation of ARF1 is implicated in various human cancers, attracting many efforts to target ARF1 pharmacologically by small molecules for anti-tumor treatments [36][37][38][39] . Additionally, ARF1 has not been found in previous AP-MS-based studies of the potential M cellular interactome [25][26][27][28] , which also motivated our further validation of the interaction.…”