Targeting cancer by Siglecs

J. Clin. Invest. https://doi.org/10.1172/JCI120612 (2018)

Immune checkpoint inhibition has shown success in a subset of patients and for certain cancers; however, the majority of patients fail to respond, emphasizing the need to identify novel molecular targets. In the Journal of Clinical Investigation, Läubli and colleagues find that the immunoregulatory receptor Siglec-9 is expressed at very low levels on human peripheral blood T cells but is fairly consistently upregulated on T cells infiltrating certain types of tumors, such as non–small-cell lung carcinoma (NSCLC). Surprisingly, Siglec-9⁺ tumor-infiltrating lymphocytes do not seem to be classically exhausted; however, tumors expressing sialoglycan ligands can inhibit T cell activation in a Siglec-9-dependent manner. A transgenic mouse tumor model shows that ligation of Siglec-9 on T cells impairs tumor control. Finally, when patients with NSCLC are stratified as Siglec-9^hi versus Siglec-9^lo, the Siglec-9^lo cohort shows better survival. Targeting Siglecs on T cells might therefore represent a promising avenue for improving cancer immunotherapies.