Targeting Sialidase to PD1 Enhances T cell Function and Tumor Control

Area of Science:

• Immunology
• Oncology
• Glycobiology

Background:

• Immune checkpoint inhibitors like anti-PD1 (programmed cell death protein 1) have revolutionized cancer therapy by boosting T cell responses.
• Tumors employ diverse mechanisms to evade immune detection, including the overproduction of immunosuppressive sialic acid-containing glycans (sialoglycans).
• Sialoglycans can inhibit T cell activation by engaging inhibitory Siglec receptors and dampening costimulatory CD28 signaling, creating a polypharmacological barrier to immune clearance.

Purpose of the Study:

• To develop a novel therapeutic strategy by conjugating sialidase to anti-PD1 (αPD1-S) to simultaneously block PD1 and degrade immunosuppressive sialoglycans.
• To investigate the efficacy of αPD1-S in enhancing T cell-mediated anti-tumor immunity and improving tumor control in preclinical cancer models.

Main Methods:

• Conjugation of sialidase enzyme to an anti-PD1 antibody to create αPD1-S.
• Glycan profiling to confirm targeted desialylation of immune cells.
• Functional assays to assess T cell activation, cytotoxic capacity, macrophage polarization, and T cell exhaustion.
• Evaluation of melanoma tumor growth in a preclinical model treated with αPD1-S, anti-PD1, or control.

Main Results:

• Targeted degradation of sialoglycans on PD1-expressing immune cells was confirmed.
• αPD1-S treatment significantly enhanced T cell activation and cytotoxic capacity.
• In a melanoma model, αPD1-S promoted inflammatory macrophage polarization and reduced T cell exhaustion.
• The combined αPD1-S therapy demonstrated superior tumor growth restriction compared to anti-PD1 alone.

Conclusions:

• Simultaneous blockade of PD1 and degradation of sialoglycans represents a potent strategy to overcome tumor immune evasion.
• αPD1-S enhances anti-tumor immune responses by improving T cell function and modulating the tumor microenvironment.
• This novel dual-action immunotherapy holds promise for improving treatment outcomes in refractory cancers.