Barkal et al. discovered that a high level of expression of MHC class I molecules on the surface of tumor cells provides protection against phagocytosis by macrophages, mediated by interaction between the LILRB1 inhibitory receptor on the surface of macrophages and the β2-microglobulin component of the MHC class I molecule, independent of the MHC-I allele. Disrupting the MHC class I/LILRB1 axis, similar to disruption of the CD47/SIRPα axis, enhances phagocytosis of tumor cells in vitro and in vivo.

Exciting progress in the field of cancer immunotherapy has renewed the urgency of the need for basic studies of immunoregulation in both adaptive cell lineages and innate cell lineages. Here we found a central role for major histocompatibility complex (MHC) class I in controlling the phagocytic function of macrophages. Our results demonstrated that expression of the common MHC class I component beta2-microglobulin (beta2M) by cancer cells directly protected them from phagocytosis. We further showed that this protection was mediated by the inhibitory receptor LILRB1, whose expression was upregulated on the surface of macrophages, including tumor-associated macrophages. Disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo, which defines the MHC class I-LILRB1 signaling axis as an important regulator of the effector function of innate immune cells, a potential biomarker for therapeutic response to agents directed against the signal-regulatory protein CD47 and a potential target of anti-cancer immunotherapy.

Author Info: (1) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (2) Institute for Stem Cell Biology and Regenerative

Author Info: (1) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (2) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Brigham and Women's Hospital, Boston, MA, USA. (3) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (4) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (5) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (6) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (7) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (8) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (9) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (10) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (11) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (12) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (13) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (14) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. (15) Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA. (16) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (17) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. irv@stanford.edu. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford, CA, USA. irv@stanford.edu. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. irv@stanford.edu. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. irv@stanford.edu. (18) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. rmaute@stanford.edu. Ab Initio Biotherapeutics, South San Francisco, CA, USA. rmaute@stanford.edu.

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