Many pathological contexts are characterized by an abnormally acidic pH. These include sites of inflammation in autoimmune conditions, the inflamed airway in respiratory diseases 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 key member of this family is GPR65 which has been shown to be highly expressed on cells of both the innate and adaptive immune systems.
Click on the video below for an explanation of Pathios’ novel Macrophage Conditioning approach to targeting the innate immune system in cancer.
In many cancers, the local tumour microenvironment becomes acidified due to the 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. Markers of a highly glycolytic tumour microenvironment are also predictive of an inadequate response to immunotherapy.
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. This occurs through induction of the transcriptional repressor, ICER (inducible cAMP early repressor), which in turn, binds to the promoters of a host of pro-inflammatory genes to suppress their expression (see below).
Schematic representation showing the mechanism by which GPR65 activation leads to the suppression of cytokine levels in macrophages. Activation of GPR65 leads to an elevation in cAMP and an induction of ICER. ICER then binds to the promoters of a host of pro-inflammatory cytokine genes to inhibit their expression.
The therapeutic potential of suppressing the GPR56-ICER pathway in cancer is underscored by the effect of a coding variant in the human GPR65 gene which causes a reduction in receptor signalling. Patients who are homozygous for this coding change (∼1.5% of all cancer sufferers) exhibit a significant survival advantage compared to other genotypes across multiple tumour types (see below). This survival advantage is present even in the face of highly glycolytic tumours that would be predicted to respond poorly to current T-cell checkpoint immunotherapies. These observations provide compelling evidence that blockade of GPR65, by virtue of counteracting the profound immunosuppressive nature of TAMs that is not addressed by existing immunotherapies, will have significant clinical impact in a large number of cancer patients.
The minor allele of rs3742704 corresponds to a coding change from an isoleucine to a leucine at position 231 in GPR65 (I231L). Patients homozygous for this variant, which leads to a reduction in receptor signalling, exhibit a significant survival advantage across multiple cancers represented in The Cancer Genome Atlas (TCGA).
In CD4+ T cells GPR65 signalling is thought to bias cell differentiation toward a pathogenic Th17 cell fate, resulting in increased inflammation in certain autoimmune disease settings. This is consistent with the finding that common genetic variants in the GPR65 gene cause an increased risk of certain autoimmune diseases such as Multiple Scelosis (MS) and Ankylosing Spondylitis (AS). By suppressing the signalling of GPR65 in Th17 cells Pathios’ drugs may have further utility in these autoimmune conditions.