Aberrantly increased cell-surface sialylation is a recurrent feature in human cancers and contributes to immune evasion. The authors examined how sialoglycans present on human T cells, with emphasis on alpha2,3-sialylation, act as a cell-intrinsic brake on T cell function. They position sialidase-based approaches as a therapeutic strategy to remove these sialic-acid–containing glycans and thereby disrupt this glyco-checkpoint.
In co-cultures of healthy donor peripheral blood mononuclear cells (PBMCs) with target tumor cells, enzymatic removal of sialic acids increased multiple measures of T cell responsiveness. Desialylation enhanced T cell activation and proliferation, elevated cytokine production, and improved tumor-cell killing mediated by bispecific T cell engagers (TCEs). These findings establish that modification of surface sialoglycans on human T cells can potentiate effector functions in a mixed PBMC setting.
The authors extended their observations to primary patient material by testing chronic lymphocytic leukemia (CLL) PBMCs ex vivo. Combining enzymatic sialidase treatment with the CD20-directed TCE glofitamab produced an augmented cytotoxic effector transcriptional program in autologous T cells. This result indicates that targeting sialylation can boost the transcriptional hallmarks of cytotoxicity in patient-derived T cells when paired with a clinically relevant bispecific engager.
To connect cell-surface glycan patterns with transcriptional changes at the single-cell level, investigators combined single-cell RNA sequencing with lectin-based CITE-seq. This integrated dataset allowed linking treatment-induced transcriptional states to lectin-defined glycan signatures on the same individual cells. The combined approach enabled identification of which T cell subsets carry particular sialoglycan motifs and how those subsets respond transcriptionally to combined sialidase and TCE treatment.
Analysis of the single-cell data highlighted that less-differentiated T cell subsets—particularly naive T cells and, to a lesser extent, central memory T cells—displayed elevated baseline alpha2,3-sialylation signatures. These same subsets showed the clearest transcriptional responses when treated with glofitamab plus sialidase, suggesting that surface sialylation acts as a subset-specific restraint on activation and effector differentiation. The findings support the concept that engaging less-differentiated T cells while reducing their sialylation may improve bispecific engager efficacy.
Within their analyses, the authors identified CD43 as a prominent carrier of alpha2,3-linked sialoglycans on T cells. Functional experiments showed that deletion of CD43 attenuated the enhancement of T cell activation that normally follows sialidase treatment, linking a specific glycoprotein to the observed regulatory effect. This result implicates CD43 as a mechanistic contributor to how surface sialylation restrains human T cell activation in the context of TCE stimulation.
Collectively, the data indicate that T cell surface sialylation is a cell-intrinsic, subset-restricted mechanism that limits responses to bispecific engagers. The authors propose that combining sialidase with TCEs, particularly those directed to engage less-differentiated T cell populations such as naive cells, warrants further testing as a strategy to enhance antitumor immunity. The ex vivo results with CLL PBMCs and the single-cell linkage of glycan signatures to transcriptional programs form the experimental rationale for such combination approaches.
These findings are reported in a preprint and have not undergone peer review. The source discloses competing interests for several authors and indicates ERC funding (grant 955575). Specific experimental details, quantitative data, and methodological parameters (for example, precise sialidase conditions, donor numbers, statistical values) are not reproduced here beyond what was summarized in the source abstract; readers should consult the full preprint and supplementary material for complete methods and results.