Local pH changes in human pathology

Many pathological contexts are characterized by an abnormally acidic pH. These include sites of inflammation in autoimmune conditions, the inflamed airway in respiratory diseases, areas of wound healing and the tumour microenvironment. Far from being benign this low pH signals to local immune cells through a family of acid-sensing GPCRs that are enriched on their cell surface. A particular key member of this family is GPR65 which has been shown to be highly expressed on cells of both the adaptive and innate immune systems.

Autoimmune disease

In CD4+ T cells GPR65 signalling is thought to bias cell differentiation toward a pathogenic Th17 cell fate, resulting in elevated cytokine secretion and increased inflammation in autoimmune disease. This is consistent with the finding that common genetic variants in the GPR65 gene cause an increased risk of certain autoimmune diseases. Pathios is developing therapies that will suppress the signalling of GPR65 in Th17 cells thereby providing a benefit across a host of autoimmune conditions.

Immuno-oncology

In some cancers acidification of the local tumour microenvironment is caused by a well known metabolic switch from oxidative phosphorylation to anaerobic glycolysis. The highly glycolytic nature of certain tumours can be readily detected in serum blood samples from patients as an elevation in the enzyme lactate dehydrogenase (LDH). LDH levels can be routinely assessed as a prognostic biomarker with high levels being predictive of poor outcomes and treatment responses. At the level of the local tumour microenvironment low pH signals to GPR65 on tumour associated macrophages (TAMs) to cause a shift in their characteristics toward a tumour-permissive, non-immune-stimulating phenotype. Blockade of GPR65 in this setting will counteract this effect leading to infiltration of the tumour with immune-stimulating TAMs, consequently supporting an eradication of tumour cells by the host immune system.