The MHC:LILRB1 axis suppresses macrophage phagocytosis and is a target for cancer immunotherapy

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The MHC:LILRB1 axis suppresses macrophage phagocytosis and is a target for cancer immunotherapy

Amira A. Barkal1, Kipp Weiskopf1, Benyamin Rosental1, Phoebe Y. Yiu1, Nan G. Ring1, Jonathan M. Tsai1, Sydney R. Gordon1, Kelly M. McKenna1, Kevin S. Kao1, Benson D. George1, Po Yi Ho1, Robin Z. Cheng1, James Y. Chen1, Aaron M. Ring5, Irving L. Weissman1,2,3,4*, Roy L. Maute1*

1Institute for Stem Cell Biology and Regenerative Medicine, 2Ludwig Center for Cancer Stem Cell Research and Medicine, 3Stanford Cancer Institute, Stanford University School of Medicine, 4Department of Pathology, Stanford University School of Medicine, Stanford CA 94305, USA., 5Department of Immunobiology, Yale University School of Medicine, New Haven CT, USA.

*Co-corresponding authors

Exciting progress in the field of cancer immunotherapy has renewed the urgency of having a detailed, mechanistic understanding of immune regulation in both adaptive and innate cell lineages. It has been demonstrated that immune clearance of cancer cells is regulated by a balance of pro-phagocytic and multiple anti-phagocytic, “don’t eat me,” signals. Modulating macrophage phagocytosis by blocking these inhibitory “don’t eat me” signals is a potentially powerful treatment strategy to promote cancer cell phagocytosis. Furthermore, the simultaneous engagement of both the innate and adaptive immune system holds promise to help maximize the effectiveness of anti-cancer immunotherapies. In our search for negative regulators of macrophage phagocytosis, we found MHC class I expression to be predictive of a cancer cell’s susceptibility to phagocytosis by macrophages. Our results demonstrate that MHC class I expression by cancer cells directly inhibits macrophage-mediated phagocytosis in vitro and in vivo, by engaging the ITIM-containing surface molecule LILRB1 on macrophages. In addition, we show that biologic agents that block either MHC class I or LILRB1 are sufficient to potentiate macrophage attack and prevent tumor growth in vivo. This identifies the MHC class I:LILRB1 signaling axis as a novel target for anti-cancer immunotherapy.

This work was supported by the D. K. Ludwig Fund for Cancer Research and the Stanford MSTP (NIH GM07365).


Credits: None available.

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