Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity
Hui-Ming Chen, … , Ping-Ying Pan, Shu-Hsia Chen
Hui-Ming Chen, … , Ping-Ying Pan, Shu-Hsia Chen
Published October 22, 2018
Citation Information: J Clin Invest. 2018;128(12):5647-5662. https://doi.org/10.1172/JCI97570.
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Research Article Oncology

Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity

Abstract

Tumor-associated myeloid cells maintain immunosuppressive microenvironments within tumors. Identification of myeloid-specific receptors to modulate tumor-associated macrophage and myeloid-derived suppressor cell (MDSC) functions remains challenging. The leukocyte immunoglobulin-like receptor B (LILRB) family members are negative regulators of myeloid cell activation. We investigated how LILRB targeting could modulate tumor-associated myeloid cell function. LILRB2 antagonism inhibited receptor-mediated activation of SHP1/2 and enhanced proinflammatory responses. LILRB2 antagonism also inhibited AKT and STAT6 activation in the presence of M-CSF and IL-4. Transcriptome analysis revealed that LILRB2 antagonism altered genes involved in cell cytoskeleton remodeling, lipid/cholesterol metabolism, and endosomal sorting pathways, as well as changed differentiation gene networks associated with inflammatory myeloid cells as opposed to their alternatively activated phenotype. LILRB2 blockade effectively suppressed granulocytic MDSC and Treg infiltration and significantly promoted in vivo antitumor effects of T cell immune checkpoint inhibitors. Furthermore, LILRB2 blockade polarized tumor-infiltrating myeloid cells from non–small cell lung carcinoma tumor tissues toward an inflammatory phenotype. Our studies suggest that LILRB2 can potentially act as a myeloid immune checkpoint by reprogramming tumor-associated myeloid cells and provoking antitumor immunity.

Authors

Hui-Ming Chen, William van der Touw, Yuan Shuo Wang, Kyeongah Kang, Sunny Mai, Jilu Zhang, Dayanira Alsina-Beauchamp, James A. Duty, Sathish Kumar Mungamuri, Bin Zhang, Thomas Moran, Richard Flavell, Stuart Aaronson, Hong-Ming Hu, Hisashi Arase, Suresh Ramanathan, Raja Flores, Ping-Ying Pan, Shu-Hsia Chen

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Figure 2

LILRB2 antagonism generates inflammatory macrophages in the presence of M-CSF.

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LILRB2 antagonism generates inflammatory macrophages in the presence of ...
(A) Representative bright-field microscopy images of M-CSF M(–) macrophages matured in the presence of mIgG2a or anti-LILRB2 (αLILRB2, 1 μg/ml). Original magnification, x20. (B) Representative levels of CD14 and CD163 expression by M(–) in the presence of mIgG2a (blue line) or anti-LILRB2 (red line). (C) Pooled paired MFI data from B collected from healthy donors (n = 10) over multiple experiments. (D) Secreted TNF-α and IL-10 from macrophages in C following 16-hour LPS (50 ng/ml) stimulation and detection by ELISA. (E) Fold changes in IRF3, 4, 5, and 7 mRNA expression relative to the mean value in IgG-treated immature macrophages cultured in the presence of M-CSF (50 ng/ml) for 2 days. P value was calculated using 2-tailed Student’s t test. (F) Representative PD-L1 expression in M(LPS) and M(IL-4) matured in the presence of mIgG2a (black) and anti-LILRB2 (red). (G) Pooled paired MFI data from F collected from healthy donors (n = 11) over multiple experiments. (H) Representative DC-SIGN expression of M(LPS) and M(IL-4) matured in the context of mIgG2a (black) and anti-LILRB2 (red). (I) Pooled paired MFI data from H collected from healthy donors (n = 11) over multiple experiments. P value was calculated using 2-tailed paired t test. *P < 0.05, **P < 0.005, ****P < 0.0001.