Cancer-associated mesothelial cells are regulated by the anti-Mullerian hormone axis

Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Mueurollerian hormone (AMH) while CAMCs express its receptor AMHR2, suggesting a paracrine axis. Factors secreted by cancer cells induce AMHR2 expression during their reprogramming into CAMCs in mouse and human in vitro models. Overexpression of AMHR2 in the Met5a mesothelial cell line is sufficient to induce expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMHdependent way. Finally, syngeneic cancer cells implanted in transgenic mice with Amhr2-/- CAMCs grow significantly slower than in wild-type hosts. The cytokine profile of Amhr2-/- tumor-bearing mice is altered and their tumors express less immune checkpoint markers programmed-cell-death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4). Taken together, these data suggest that the AMH/AMHR2 axis plays a critical role in regulating the pro-tumoral function of CAMCs in ovarian cancer.

Automated summary

Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment promote tumor growth and immune evasion. The paracrine axis between cancer cells expressing anti-Mueurollerian hormone (AMH) and CAMCs expressing its receptor AMHR2 plays a critical role. AMHR2 expression is induced by factors secreted by cancer cells during their reprogramming into CAMCs. Overexpression of AMHR2 induces the expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMH-dependent way. The AMH/AMHR2 axis regulates the pro-tumoral function of CAMCs in ovarian cancer.