Blocking an Enzyme in Melanoma Patients Could Overcome Resistance to Immunotherapy

Approximately 65% of patients diagnosed with melanoma are unresponsive to immunotherapy. New research suggests that blocking the HPGDS enzyme can be a viable way to improve patients’ response to immunotherapy since the activity of this enzyme contributes to immunotherapy resistance. This approach can also increase immunotherapy response in other types of cancer with similar attributes to those of melanoma.

Over the last 10 years, significant advances have been made in leveraging immunotherapy to treat melanoma and other cancers. However, more than half (65%) of melanoma patients don’t respond to immunotherapy. TAMs (tumor-associated macrophages) play a major role in this immunotherapy resistance since they hinder immune function and consequently promote the growth of tumors and their metastasis.

The team of researchers sought to reprogram TAMs so that they can no longer suppress the immune system of melanoma patients.

Doctor Rosa Trotta, who was the lead author of this research, explains that they analyzed immune response genes in melanoma patients that exhibited a positive response to immune checkpoint blockade treatments in comparison to the immune response genes of patients that didn’t respond to those treatments.

Their data revealed that those who responded to the treatments had downgraded levels of HPGDS while unresponsive patients had high levels of this enzyme.

The researchers leveraged genetic deletion to get rid of HPGDS. For the humanized models and mice used in the study, pharmacological interventions were used to suppress HPGDS. The macrophages exhibited remarkable changes since they no longer supported tumor growth. Instead, the anti-tumor activity of the treatments used was enhanced.

Professor Max Mazzone, who led the research team, explains that when they targeted the HPDGS gene, two key benefits were observed. First, T-cell recruitment to cancerous tissue and the activation of these fighter cells was boosted. Secondly, the suppression of the HPDGS gene created an opportunity for overcoming the cancer’s resistance to the treatments that were currently available.

This research suggests that melanoma and other such cancers may be better treated through interventions that block the PGD2 receptors (the receptor where the HPDGS gene is expressed) or those designed to block the HPDGS gene.

Given that this research was preclinical, its findings can only hold concrete promise if they are replicated in clinical studies. There’s still plenty to do before this new treatment approach can be tested on human subjects. In the meantime, immune-oncology companies like Calidi Biotherapeutics Inc. (NYSE American: CLDI) that already have new treatments undergoing clinical trials could offer hope to melanoma patients in need of treatments that can deliver the clinical outcomes they seek.

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