LAUSR

Drugs that target cancer stem cells (CSCs) are thought to be a critical component of any successful therapy against cancer. CSCs are responsible for chemoresistance, metastasis, and ultimately relapse of the cancer, even after an initial successful therapeutic intervention. While it is well known that CSCs are driven by some of the same major self-renewal pathways that drive embryonic stem cells, knowledge of other cellular pathways that drive CSC activity is still limited. In this work, we uncover a novel role for chemokine (C-C motif) ligand 20 (CCL20) in CSC growth and activity, expanding the role for this chemoattractant protein. We discovered that CSCs of many tumor types overexpress CCL20, which we show drives CSC self-renewal and proliferation by autocrine signaling through its receptor CCR6. Targeting this axis with a neutralizing monoclonal antibody against CCL20 significantly reduces CSC frequency and tumor initiation and growth, supporting the novel therapeutic potential of targeting the CCL20-CCR6 axis as a strategy to eliminate CSCs. Furthermore, we found that CCL20 secreted by tumor cells also strongly influences the frequencies not only of T-cells, particularly immune-suppressive regulatory T-cells (Treg) and Th17 populations, but also dendritic and neutrophil/gMDSC populations, to promote anti-tumor immunity that leads to immune-mediated inhibition of tumor growth. Strikingly, we discovered that tumor-specific CCL20 impacted not just the immune cell balance within the tumor microenvironment, but had far reaching effects into the peripheral immune system as well. Thus, our overall findings propose that CCL20 plays a dual role in the tumor environment: 1) by driving activity and tumorigenic ability of CSCs, and 2) by promoting an immunosuppressive phenotype. In this work we show that therapeutic neutralization of CCL20 can deliver a one-two punch against cancer, by directly inhibiting CSCs, and by relieving immunosuppression, thereby opening this target up as an exciting novel strategy to treat cancer. Citation Format: Lilian E. van Vlerken-Ysla, Jonathan Rios-Doria, James Moynihan, Lu Shan, Robert E. Hollingsworth, Ronald Herbst, Elaine M. Hurt. Targeting the CCL20-CCR6 axis as a novel opportunity to stimulataneously modulate cancer stem cells and the tumor-immune infiltrate by a dual anti-cancer mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4779. doi:10.1158/1538-7445.AM2017-4779