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The Fibronectin-ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells.

ABSTRACT: Suppressive myeloid cells inhibit antitumor immunity by preventing T-cell responses. Immunoglobulin-like transcript 3 (ILT3; also known as LILRB4) is highly expressed on tumor-associated myeloid cells and promotes their suppressive phenotype. However, the ligand that engages ILT3 within the tumor microenvironment and renders tumor-associated myeloid cells suppressive is unknown. Using a screening approach, we identified fibronectin as a functional ligand for ILT3. The interaction of fibronectin with ILT3 polarized myeloid cells toward a suppressive state, and these effects were reversed with an ILT3-specific antibody that blocked the interaction of ILT3 with fibronectin. Furthermore, ex vivo treatment of human tumor explants with anti-ILT3 reprogrammed tumor-associated myeloid cells toward a stimulatory phenotype. Thus, the ILT3-fibronectin interaction represents a "stromal checkpoint" through which the extracellular matrix actively suppresses myeloid cells. By blocking this interaction, tumor-associated myeloid cells may acquire a stimulatory phenotype, potentially resulting in increased antitumor T-cell responses.

SUBMITTER: Paavola KJ

PROVIDER: S-EPMC9414285 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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The Fibronectin-ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells.

Paavola Kevin J KJ Roda Julie M JM Lin Vicky Y VY Chen Peirong P O'Hollaren Kyle P KP Ventura Richard R Crawley Suzanne C SC Li Betty B Chen Hung-I H HH Malmersjö Seth S Sharkov Nikolai A NA Horner Geoffrey G Guo Wei W Kutach Alan K AK Mondal Kalyani K Zhang Zhen Z Lichtman Joshua S JS Song Christina C Rivera Lee B LB Liu Wenhui W Luo Jian J Wang Yan Y Solloway Mark J MJ Solloway Mark J MJ Allan Bernard B BB Kekatpure Avantika A Starck Shelley R SR Haldankar Raj R Fan Bin B Chu Chun C Tang Jie J Molgora Martina M Colonna Marco M Kaplan Daniel D DD Hsu Jer-Yuan JY

Cancer immunology research 20210823 11

Suppressive myeloid cells inhibit antitumor immunity by preventing T-cell responses. Immunoglobulin-like transcript 3 (ILT3; also known as LILRB4) is highly expressed on tumor-associated myeloid cells and promotes their suppressive phenotype. However, the ligand that engages ILT3 within the tumor microenvironment and renders tumor-associated myeloid cells suppressive is unknown. Using a screening approach, we identified fibronectin as a functional ligand for ILT3. The interaction of fibronectin ...[more]

PMID: 34426457

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Dataset Information

The Fibronectin-ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells.

Publications

The Fibronectin-ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells.

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