Researchers at the Icahn School of Medicine at Mount Sinai have discovered that ovarian cancer cells produce interleukin-4 (IL-4) to create a protective tumor microenvironment, enabling the cancer to resist immunotherapy. The findings, published in Cell, suggest that blocking IL-4 could enhance the effectiveness of existing immunotherapies for ovarian cancer.
The research team, led by Alessia Baccarini, PhD, and Brian D. Brown, PhD, employed spatial genomics technology and preclinical animal models, along with tumor specimens from ovarian cancer patients, to investigate the mechanisms of immunotherapy resistance. Ovarian cancer has a five-year survival rate of less than 50%, and while immunotherapies like pembrolizumab have shown promise in other cancers, they have had limited success in ovarian cancer, with objective response rates below 10%.
IL-4's Role in Immunosuppression
The study revealed that ovarian cancer cells secrete IL-4, which is typically associated with asthma and eczema, to suppress the immune response within the tumor microenvironment. This immunosuppression prevents immune cells, particularly T cells, from infiltrating and attacking the tumor. "Our studies, implicating IL-4 as a mechanism of anti-PD1 resistance and the synergistic therapeutic benefit of anti-PD-1 and anti-IL-4R, suggest OvCa may also be a good candidate for combined PD1 and IL4R blockade," the researchers noted in their paper.
To identify regulators of ovarian cancer immunity, the team used Perturb-map, a spatial functional genomics screen focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Their experiments showed that removing the IL-4 gene from ovarian cancer cells made the tumors susceptible to anti-PD-1 therapy. "Surprisingly, the IL-4-deficient cancer cells were eliminated by the immune system even when mixed within tumors containing IL-4-producing cancer cells," said Brown.
Preclinical Evidence and Clinical Implications
In preclinical studies, the researchers tested a combination of anti-PD-1 and IL-4 receptor-blocking drugs in mice with aggressive metastatic ovarian cancer. The combination treatment significantly extended survival compared to anti-PD-1 therapy alone. Additional studies showed that IL-4 programs macrophages, a type of immune cell, into protectors of the cancer cells, preventing T cells from killing the cancer cells. Blocking IL-4 reversed this effect, making the cancer cells vulnerable to immune attack.
Analysis of human ovarian tumor specimens confirmed that cancer cells also produced IL-4. Single-cell RNA sequencing data from patient tumors revealed a strong IL-4 signature in macrophages, suggesting a similar mechanism in human ovarian cancer. "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 tumor’s microenvironment, we could make these difficult-to-treat tumors more treatable," added Brown.
Future Directions
The researchers are optimistic that these findings could lead to new therapeutic strategies for ovarian cancer. Given that dupilumab, an IL-4 blocking drug, is already FDA-approved for asthma and eczema, there is potential for rapid clinical testing in combination with immunotherapy to improve survival in ovarian cancer patients. Thomas Marron, MD, PhD, is already conducting a clinical study to assess whether dupilumab can enhance anti-PD-1 immunotherapy in lung cancer patients, with some patients showing beneficial responses. The team noted in their paper, "We further demonstrate OvCa cells are the key source of IL-4 in ovarian tumors and that combining PD-1 and IL-4 receptor (IL4R) blockade converts anti-PD-1 non-responsive tumors to responsive."
