Arecoline upregulates CD155 expression to facilitate immune evasion in oral squamous cell carcinoma

Areca nut is the fourth most addictive substance worldwide and is a known Group 1 carcinogen. Chronic areca nut chewing has been strongly associated with the development of oral squamous cell carcinoma (OSCC), although the underlying carcinogenic mechanisms remain unclear.

Employing spatial multiomics technology, we recently mapped the immune microenvironment of areca nut-associated OSCC and identified a marked upregulation of the immune checkpoint molecule CD155 in these tumors. Further quantitative reverse transcription-PCR, western blotting, immunofluorescence, animal experiments, etc, explored and verified the reasons for the upregulation of CD155 caused by arecoline and the results of immune escape in OSCC.

The investigation revealed that arecoline, a bioactive component of areca nut, induces CD155 expression in OSCC cells. Through interaction with its receptor, TIGIT, CD155 suppresses CD8⁺ T cell function and activity, facilitating immune evasion in OSCC. Mechanistically, arecoline upregulates CD155 via activation of muscarinic acetylcholine receptors on the surface of OSCC cells, leading to RhoA-mediated inhibition of YAP phosphorylation. This promotes YAP nuclear translocation and phase separation, driving CD155 transcription. In both in vitro and in vivo models, blockade of the CD155-TIGIT signaling axis significantly enhanced the efficacy of immunotherapy in OSCC.

This study unveils a novel mechanism by which arecoline promotes immune evasion in OSCC and highlights promising immune therapeutic targets and strategies for the treatment of areca nut-associated OSCC.