Description

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. Weissman^1,2,3,4*, 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).