Researchers have discovered that an eczema-linked protein helps ovarian cancer manipulate its environment to resist immunotherapy, suggesting the potential for a skin drug-based treatment.

Scientists at the Icahn School of Medicine at Mount Sinai used spatial genomics technology and preclinical animal models, with tumour specimens from ovarian cancer patients further validating the findings.

The researchers found that ovarian cancer cells produce a molecule called Interleukin-4 (IL-4), which is typically associated with asthma and the skin condition eczema, also known as atopic dermatitis.

The study went on to find that the cancer cells used IL-4 to create a protective environment that kept away killer immune cells, making the tumours resistant to immunotherapy.

“It was quite stunning to us that by just blocking this one molecule, IL-4, and altering the tumour’s microenvironment, we could make these difficult-to-treat tumours more treatable”

Dupilumab, which blocks IL-4’s activity, has been approved by the Food and Drug Administration (FDA) and is already used to treat asthma and eczema. This new study suggests dupilumab or similar drugs could be repurposed to enhance immunotherapy for ovarian cancer.

Intratumoural heterogeneity

The team, led by Alessia Baccarini, Assistant Professor of Immunology and Immunotherapy, and Brian Brown, Director of the Icahn Genomics Institute, used a novel genomics technology known as Perturb-map.

Perturb-map enhances traditional gene-editing CRISPR screening – where hundreds of genes are simultaneously “perturbed” – by incorporating spatial imaging. This enables each gene’s role in controlling the tumour environment to be elucidated.

Their experiments revealed that removing the IL-4 gene from ovarian cancer cells rendered the tumours susceptible to anti-PD-1 therapy.

“Surprisingly, the IL-4-deficient cancer cells were eliminated by the immune system even when mixed within tumours containing IL-4-producing cancer cells, a phenomenon known as intratumoural heterogeneity, which also contributes to drug resistance in cancer,” said Dr Brown.

The researchers then tested a combination of anti-PD-1 and IL-4 receptor-blocking drugs in mice with aggressive metastatic ovarian cancer and found that this combination treatment significantly extended their survival.

Additional preclinical studies demonstrated that ovarian cancer uses IL-4 to program macrophages, a type of immune cell, into protectors of the cancer cells. The IL-4-programmed macrophages prevented T cells from killing the cancer cells. However, when IL-4 was blocked, the local environment surrounding the cancer cells changed, and this left the malignant cells susceptible to being eliminated by the immune system.

Making tumours more treatable

To further validate their findings, the team examined specimens from human ovarian tumour resections and saw that the patients’ cancer cells also produced IL-4. Moreover, analysis of single-cell RNA sequencing data from patient tumours – which examines how genes are expressed in cells – revealed that the macrophages displayed a strong IL-4 signature, suggesting that IL-4 is playing a similar role in human ovarian cancer and may be one of the reasons patients have not benefited from immunotherapy.

“Ovarian cancer has almost been written off as non-responsive to existing immunotherapy, so it was quite stunning to us that by just blocking this one molecule, IL-4, and altering the tumour’s microenvironment, we could make these difficult-to-treat tumours more treatable,” added Dr Brown. “This is further evidence that targeting the tumour’s neighbourhood, not just the cancer cells, can be beneficial.”

The investigators stress that clinical trials will be needed to determine whether targeting IL-4 can enhance patient outcomes.

Read the full paper ‘Ovarian cancer-derived IL-4 promotes immunotherapy resistance’.

Diana Spencer, Senior Digital Content Editor, DDW