Tumor immune cell targeting chimeras reprogram tumor-associated macrophages.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Tumor-associated macrophages (TAMs) are key regulators of immunosuppression and tumorigenesis, constituting a significant portion of solid tumors.
• Current immunotherapies, like immune checkpoint inhibitors, leverage the cancer-immune interface but face challenges with systemic immune-related adverse events.
• There is a critical need for potent and tumor-specific immunotherapies to overcome these limitations.

Purpose of the Study:

• To develop a novel therapeutic strategy for tumor-specific immunotherapy.
• To create a system that selectively targets and depletes immune checkpoint receptors from TAMs.
• To introduce a new paradigm for cancer treatment by decoupling antibody selectivity from blocking function.

Main Methods:

• Development of tumor immune cell targeting chimeras (TICTACs) comprising a CD206-targeting ligand and a nonblocking antibody against immune checkpoint receptors (e.g., SIRPα).
• Utilizing CD206, a TAM marker, for selective targeting due to its constitutive recycling between the plasma membrane and early endosomes.
• Assessing the ability of TICTACs to induce robust checkpoint degradation specifically in CD206-high macrophages.

Main Results:

• TICTACs selectively target CD206-expressing TAMs.
• Engagement of CD206 leads to efficient degradation of immune checkpoint receptors on TAM surfaces.
• Therapeutic effect is observed specifically in CD206-high macrophages, with no impact on CD206-low cells.

Conclusions:

• TICTACs represent a novel approach for developing potent, tumor-specific immunotherapies.
• This strategy offers a way to overcome the limitations of systemic immune checkpoint blockade.
• The decoupling of antibody selectivity from blocking function opens new avenues for targeted cancer treatment.