The acidic tumour microenvironment inherent to many cancers causes a profound immunosuppression of infiltrating immune cells. This disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumour associated macrophages (TAMs), where acidity is sensed by the cell-surface receptor, GPR65, leading to an induction of the transcriptional repressor, ICER (inducible cAMP early repressor), and the widespread suppression of pro-inflammatory mediators such as TNFα, IL-6 and IL-12. Pathios is developing drugs to block GPR65 and prevent this signalling, thereby conditioning macrophages toward a pro-inflammatory, immune-stimulating phenotype that can reignite an effective anti-tumour immune response and harness the power of the innate immune system against cancer.
GPR65 is a critical mediator of low pH induced immunosuppressive signalling in tumor associated macrophages: Human target validation of GPR65 as a novel innate immune checkpoint and discovery of potent, selective GPR65 antagonists