Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity
Menée à l'aide d'un modèle murin, cette étude met en évidence l'intérêt de cibler les récepteurs Siglec-7 et Siglec-9 pour augmenter la réponse antitumorale du système immunitaire
Targeting myeloid cells represents a promising strategy to augment antitumor immunity and overcome resistance to existing T cell-targeting therapies. However myeloid checkpoints that can be effectively used as immunotherapy targets are still lacking. Here, we demonstrate the therapeutic potential of targeting Siglec-7 and Siglec-9 to enhance antitumor immunity in vivo. Using an immunocompetent mouse model humanized for Siglec-7/9, we show that these receptors inhibit the endogenous antitumor immune response in a tissue-specific manner. These Siglecs also restrict the response to tumor-targeting and checkpoint-targeting antibodies, highlighting their significance in combinatorial approaches to immunotherapy. Finally, we show that Siglec-7/9 blockade can significantly reduce tumor burden in vivo, supporting the use of antibodies targeting Siglec-7/9 to therapeutically enhance antitumor immunity.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.All study data are included in the article and SI Appendix.