Blocking enzyme could lead to improved treatment pathway in resistant form of melanoma

HPGDS enzyme plays key role in resistance of immunotherapy in various cancers 

Up to 65% of patients with melanoma do not respond to treatment with immunotherapy. However, a research team led by Professor Max Mazzone at VIB-KU Leuven Center for Cancer Biology – the Flemish Institute of Biotechnology, Centre for Cancer Biology at the Catholic University, Leuven – has discovered that the enzyme hematopoietic prostaglandin D synthase (HPGDS) – moderates resistance to immunotherapies.

Immuno-oncology has seen important therapeutic advances in recent years, particularly in treatments for aggressive forms of melanoma. Still around two-thirds of melanoma patients do not respond to immune checkpoint blockade (ICB) therapies.

It is thought that immunosuppression induced by tumour-associated macrophages (TAMs) may be central to this process. TAMs impede the correct functioning of the immune system and so promote an environment that is more positive to tumour growth and metastasis. Consequently, to improve oncology therapies efforts have been made to reprogramme TAM phenotype away from their immunosuppressive state.

Professor Mazzone and his team have focused their work on the enzyme HPGDS which is produced by TAMs. HPGDS promotes the formation of a metabolite called prostaglandin D₂ (PGD₂), which has the effect of blocking the activity of T-cells that attack tumours.

“By analysing the expression of genes related to the immune response in patients who responded to immune checkpoint blockade therapies compared to those who did not, we found that HPGDS levels were high in non-responding patients during treatment.

“Whereas [HPGDS was] downregulated if the treatment was working and T-cells were then activated against the tumour,” said Dr. Rosa Trotta, first author of the study. 

Using genetic deletion of HPGDS in macrophages and deploying pharmacological inhibitors in human and mouse models, the team demonstrated a shift in the behaviour of the macrophages. Previously they had promoted growth in tumours but after the HPGDS suppression supported a more robust anti-tumoral immune response.

“Targeting HPGDS not only enhanced the recruitment and activation of T-cells per se but also showed promise in overcoming resistance to existing therapies.

“Our findings suggest that blocking HPGDS – or the two downstream receptors – may be a potential strategy for improving [novel] treatment options for melanoma patients and perhaps others facing similar challenges,” said Professor Mazzone.

The study indicates that HPGDS inhibitors – or PGD₂ receptor – blockers could be therapeutic agents, either alone or in combination with existing treatments for melanoma and other cancers, such as pancreatic ductal adenocarcinoma, that show similar resistance mechanisms.