Targeted glycan degradation potentiates cellular immunotherapy for solid tumors.

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Chimeric antigen receptor T (CAR-T)-cell immunotherapy shows success in blood cancers but limited efficacy in solid tumors.
• Solid tumors often evade immune detection through mechanisms like glyco-immune checkpoints.

Purpose of the Study:

• To develop a strategy enhancing CAR-iMac therapy for solid tumors by targeting cancer cell sialoglycans.
• To investigate the therapeutic potential of combining cancer cell desialylation with CAR-iMac adoptive cellular therapy.

Main Methods:

• Designed tumor-targeting molecule-sialidase conjugates to remove sialoglycans from cancer cells.
• Evaluated the impact of desialylation on CAR-iMac infiltration, activation, and anti-tumor efficacy in mouse models.
• Investigated the role of sialic acid-binding immunoglobulin-like lectin (Siglec)-5 and Siglec-10 checkpoints.

Main Results:

• Desialylation enhanced CAR-iMac infiltration and activation against solid tumors.
• Combined desialylation and CAR-iMac therapy demonstrated significant anti-tumor effects and prolonged survival in mice.
• Therapeutic effects were linked to the blockade of Siglec-5/Siglec-10 checkpoints on macrophages.

Conclusions:

• Desialylation combined with CAR-iMac immunotherapy offers a promising approach to treat solid tumors.
• This strategy converts immune-excluded "cold tumors" into immune-sensitive "hot tumors".
• Inhibiting glycoimmune checkpoints presents a new avenue for developing effective cancer immunotherapies.