High EP2/EP4 Expression Linked to Immune-Suppressing Tumor Microenvironment

Researchers in Japan have identified the mechanism by which active inflammation and immunosuppression in the tumor microenvironment (TME) work in parallel to prevent immune cells from reaching and destroying cancerous cells.

Active inflammation generally promotes immune activation. However, in the TME, active inflammation occurs in parallel with immunosuppression, and both contribute to tumor growth. Why inflammation does not lead to immune activation in TME remains unclear.

Using the immune checkpoint inhibitor-insensitive mouse cancer model and single-cell RNA sequencing, a team at Kyoto University has shown that PGE2-EP2/EP4 signaling simultaneously promotes active inflammation by inducing expression of the NF-κB genes in myeloid cells and elicits immunosuppression by driving the mregDC (mature DC enriched in immunoregulatory molecules)-Treg (regulatory T cell) axis for Treg recruitment and activation in the tumor.

Publicly accessible data indicate that some patients with either lung, ovarian, breast, or liver cancers have high EP2/EP4 expression levels. "What is important is that EP2/EP4 expression was positively correlated with the expression of genes related to Treg recruitment and activation in these cancer patients," says lead author Dean Thumkeo of the Department of Drug Discovery Medicine.

Using single-cell RNA sequencing, Thumkeo and colleagues analyzed the action mechanism of the inhibitors of prostaglandin E2 receptor in mouse models. Results showed reduced gene expression of regulatory T cell or Treg, a strong immunosuppressive cell, involved in immunosuppression.

"We discovered that EP2/EP4 inhibitors suppressed tumor growth in mouse models by allowing Treg to infiltrate the tumor and activate there," Thumkeo says.  This correlation suggests to the researchers that patients with high EP2/EP4 expression suffer from a TME that highly suppresses the immune system, suggesting that cancer treatment employing EP2/EP4 inhibitors might benefit some patients with these cancers.

Currently, immune checkpoint inhibitors (ICIs) that target the immune system rather than cancer cells appear to be the new go-to cancer treatment. Typically, about a quarter of cancer patients show a significant response to ICIs. For the remaining portion of patients, EP2/EP4 inhibitors may be a potential alternative.

"For now, the discovery of the anti-immunosuppressants gives us a new way forward in exploring cancer therapeutics beyond ICIs," concludes Thumkeo.

The paper, entitled "PGE2-EP2/EP4 signaling elicits immunosuppression by driving the mregDC-Treg axis in inflammatory tumor microenvironment" was published recently in the peer review journal Cell Reports.