Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity.

Autor:	Ibarlucea-Benitez I; Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065., Weitzenfeld P; Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065., Smith P; Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065., Ravetch JV; Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065 ravetch@rockefeller.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jun 29; Vol. 118 (26).
DOI:	10.1073/pnas.2107424118
Abstrakt:	Given the role of myeloid cells in T cell activation and in the antitumor response, targeting checkpoint molecules expressed on this population represents a promising strategy to augment antitumor immunity. However, myeloid checkpoints that can be effectively used as immunotherapy targets are still lacking. Here, we demonstrate the therapeutic potential of targeting the myeloid receptors Siglec-7 and Siglec-9 in vivo. By using a humanized immunocompetent murine model, we demonstrate that human Siglec-7 and Siglec-9, in addition to the murine homolog Siglec-E, inhibit the endogenous antitumor immune response, as well as the response to tumor-targeting and immune checkpoint inhibiting antibodies in vivo. The impact of these Siglecs on tumor progression is highly dependent on the anatomical distribution of the tumor and, as a consequence, the local tumor microenvironment, as tumors with a more immune-suppressive tumor microenvironment are less sensitive to Siglec perturbation. Finally, to assess the potential of these two receptors as targets for immunotherapy, we developed Fc engineered blocking antibodies to Siglec-7 and Siglec-9 and demonstrate that Siglec-7 and Siglec-9 blockade can significantly reduce tumor burden in vivo, demonstrating the therapeutic potential of targeting these two receptors. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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