Article ; Online: ILT2 and ILT4 Drive Myeloid Suppression via Both Overlapping and Distinct Mechanisms.
2024 Volume 12, Issue 5, Page(s) 592–613
Abstract: Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune-suppressive receptors that play ...
| Abstract | Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune-suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contribution of ILT2 and ILT4 to immune inhibition in the context of solid tumor tissue has not been fully explored. We present evidence that both ILT2 and ILT4 contribute to myeloid inhibition. We found that although ILT2 inhibits myeloid cell activation in the context of trans-engagement by MHC-I, ILT4 efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement. In a 3D spheroid tumor model, dual ILT2/ILT4 blockade was required for the optimal activation of myeloid cells, including the secretion of CXCL9 and CCL5, upregulation of CD86 on dendritic cells, and downregulation of CD163 on macrophages. Humanized mouse tumor models showed increased immune activation and cytolytic T-cell activity with combined ILT2 and ILT4 blockade, including evidence of the generation of immune niches, which have been shown to correlate with clinical response to immune-checkpoint blockade. In a human tumor explant histoculture system, dual ILT2/ILT4 blockade increased CXCL9 secretion, downregulated CD163 expression, and increased the expression of M1 macrophage, IFNγ, and cytolytic T-cell gene signatures. Thus, we have revealed distinct contributions of ILT2 and ILT4 to myeloid cell biology and provide proof-of-concept data supporting the combined blockade of ILT2 and ILT4 to therapeutically induce optimal myeloid cell reprogramming in the tumor microenvironment. |
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| MeSH term(s) | Receptors, Immunologic/metabolism ; Animals ; Humans ; Mice ; Tumor Microenvironment/immunology ; Leukocyte Immunoglobulin-like Receptor B1/metabolism ; Myeloid Cells/immunology ; Myeloid Cells/metabolism ; Membrane Glycoproteins/metabolism ; Cell Line, Tumor ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; Myeloid-Derived Suppressor Cells/immunology ; Myeloid-Derived Suppressor Cells/metabolism ; Antigens, CD |
| Chemical Substances | Receptors, Immunologic ; LILRB4 protein, human ; LILRB2 protein, human ; Leukocyte Immunoglobulin-like Receptor B1 ; Membrane Glycoproteins ; LILRB1 protein, human ; LILRB3 protein, human ; Antigens, CD |
| Language | English |
| Publishing date | 2024-03-13 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2732489-8 |
| ISSN | 2326-6074 ; 2326-6066 |
| ISSN (online) | 2326-6074 |
| ISSN | 2326-6066 |
| DOI | 10.1158/2326-6066.CIR-23-0568 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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