Many pathological contexts are characterised by an abnormally acidic pH. These include sites of inflammation in autoimmune conditions, the inflamed airway in respiratory diseases and the tumour microenvironment (TME). 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 exclusively expressed on cells of immune system.
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Whilst the advent of T-cell checkpoint inhibitors has revolutionised cancer treatment for many tumour types, it remains the case that the majority of patients have an inadequate response to these therapies. The reason for this poor response rests with the key features of the immunologically hostile tumour microenvironment (TME) that is present in many solid cancers. These features include a high angiogenesis and wound healing gene signature, a reduced expression of proinflammatory cytokines and chemokines and consequent exclusion of important effector cells, a suppression of interferon and antigen presentation genes, and a dominance by immunosuppressive tumour associated macrophages (TAMs).
The critical features of the immunologically hostile TME that explain a lack of or poor response to currently approved immunotherapies.
In many cancers the TME becomes acidified due to the well-known metabolic switch from oxidative phosphorylation to anaerobic glycolysis and the high expression of acidifying enzymes. At the level of the local TME, low pH signals to GPR65 on TAMs to cause a shift in their characteristics toward a tumour-promoting, non-immune-stimulating phenotype (see below). This occurs through a host of downstream transcriptional changes and can explain the critical features of the immunologically hostile TME described above. At Pathios, we are developing first-in-class drugs to suppress GPR65 signalling and therefore address the most pressing issue in cancer immunology today: delivering an immunotherapy treatment to the large number of patients who do not currently respond to approved T-cell checkpoint inhibitors.
Schematic representation showing the mechanism by which GPR65 activation is the key determinant of the immunosuppressive macrophage phenotype and dictates the properties of the immunologically hostile TME.
The therapeutic potential of inhibiting the GPR65 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 robust human genetic validation and compelling evidence that blocking GPR65 will have a significant clinical impact in a large number of cancer patients. Furthermore, inhibiting GPR65 has the potential to deliver profound monotherapy activity as evidenced by our extensive preclinical pharmacology work carried out in a range of syngeneic mouse models. These features are unique amongst approaches that attempt to target immunosuppressive TAMs and the immunologically hostile TME.
The minor allele of rs3742704 corresponds to a coding change from an isoleucine to a leucine at position 231 in GPR65 (I231L). Patients that are 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 addition to cancer, GPR65 plays a key role in a host of other immunological diseases as evidenced by a rich array of human genetic evidence. These include inflammatory and autoimmune diseases such as Inflammatory Bowel Disease and Ankylosing Spondylitis as well as CNS disorders with an immunological involvement such as Multiple Sclerosis and Parkinson’s Disease. At Pathios we have created a proprietary and extensive toolkit around GPR65 which enables us to explore the potential for small molecule GPR65 modulators in these additional diseases.