Targeting PAR-2 with a negative allosteric modulator increases tumor antigen presentation and potentiates anti-PD-1 immunotherapy.

backgroundIdentifying the mechanisms underlying resistance to immune checkpoint inhibitors (ICIs) has become a major focus in cancer immunotherapy. Our previous work identified

methodsActivated PAR-2 levels in patient serum were quantified using a protein-based assay to assess PAR-2 activation and its association with clinical outcomes. The therapeutic impact of PAR-2 targeting was evaluated in preclinical tumor models using either global F2rl1 gene deletion or pharmacological inhibition with the selective, insurmountable PAR-2 negative allosteric modulator I-117, in combination with anti-PD-1 therapy. To further characterize immune changes associated with PAR-2 targeting, immune cell populations, cytokine profiles, and transcriptional programs were analyzed in tumors and/or tumor-draining lymph nodes (tDLNs). Ex vivo co-culture assays were performed to assess antigen presentation by CD11c

resultsActivated PAR-2 levels were significantly elevated in the serum of patients with cancer across multiple tumor types and were associated with reduced survival in patients with lung cancer treated with pembrolizumab plus platinum-based chemotherapy. In preclinical models, both global F2rl1 deletion and pharmacological inhibition of PAR-2 with I-117 significantly potentiated the therapeutic efficacy of anti-PD-1 treatment. PAR-2 inhibition altered the tumor immune microenvironment, characterized by a reduction in putative immunosuppressive myeloid cell populations and increased activation of CD8

conclusionsThese findings support PAR-2 inhibition as a strategy to enhance the efficacy of PD-1 blockade, providing a rationale for their combined use in cancer immunotherapy.