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Research 2024/07/01
Computationally and evolutionarily enhanced immune cell engager for anticancer immunotherapy

Computational design, directed evolution, and recombinant protein technology have opened up new venues for therapeutic designs for cancer treatment. The latest research from the teams of Dr. Mou Yun and Dr. Jack Hu, Associate Research Fellow at the Institute of Biomedical Sciences, Academia Sinica, showcases a novel therapeutic protein design that can activate both cytotoxic T lymphocytes and natural killer (NK) cells in the tumor microenvironment for synergistic tumor containment. The therapeutic protein, named superantigen-based tri-functional yeast-display-enhanced multivalent immune cell engager (STYMIE), is comprised of three separated components, including a directed-evolution-enhanced superantigen for CD8 T cell and NK cell activation, a computationally designed cytokine for sustained immune cell stimulation, and a tumor-homing antibody for targeted delivery. The study demonstrates effective suppression of immune-suppressive tumor types, including colorectal cancer, breast cancer, and lung cancer, and it further reveals insights into immune cell activation mechanism behind superantigens. This research highlights new design principles in immune cell engagers and has been published in "Advanced Science" on June 28th, 2024.

Tumors often leverages multiple immune-suppressive mechanisms to escape from immune attacks, and efforts to recruit immune cells into the tumor microenvironment have inspired development of tumor-targeted immune cell engagers toward bridging T lymphocytes and cancer cells. This study explored a new design strategy that leverages superantigens known to activated multiple immune cell types. To increase the functionality of superantigens, the researchers adopted a yeast-display directed evolution technique to identify mutants with enhanced affinity to immunoreceptors.  The researchers further fused the enhanced superantigen to an Fc receptor, immunological cytokine, and a tumor-targeting nanobody. The resulting chimeric protein enables extended systemic circulation, robust tumor accumulation, and CD8 T cell and NK cell recruitment to the tumor microenvironment, thereby promoting the elimination of cancer cells.

Dr. Yao-An Yu, the lead researcher in this study, further discovered the underlying molecular mechanism behind superantigen-mediated T cell activation. Through the adoption of CRISPR knock-out technology for immunoreceptor screen, Yao-An identified CD2 and CD58 as primary ligands that engage with superantigens. Preservation of D55G on superantigen mutants was also identified as a critical factor for T cell receptor engagement, as its alteration was observed to abrogate T cell activation.

This research opens up new possibilities in cancer treatment as CD8 T cells and NK cells work synergistically to prevent tumor immune escape. While CD8 T cells can recognize mutant neoantigens displayed by the major histocompatibility complex (MHC) on cancer cells, many cancer cells can downregulate MHC expression to minimize CD8 T cell engagement. These low-MHC-expressing tumor cells, however, are particularly susceptible to NK cell attack. The STYMIE developed in the study engages with both CD8 T cells and NK cells to impede tumor progression. The work is the culmination of Dr. Mou's continuing commitment to fusion protein engineering, which has ushered in a variety of protein design and development strategies.

This research was published in Advanced Science on June 28th, 2024 (IF: 15.1), under the title "High-Affinity Superantigen-Based Trifunctional Immune Cell Engager Synergizes NK and T Cell Activation for Tumor Suppression." The main authors include graduate student Yao-An Yu and Research Assistant Wen-Ching Lin. Collaborative investigators include Dr. Che-Ming Jack Hu from the Institute of Biomedical Sciences (IBMS) at Academia Sinica and Dr. Chung-Yuan Mou from the Department of Chemistry, National Taiwan University. Dr. Mou Yun was a former Associate Research Fellow at IBMS. Dr. Mou unfortunately passed away on 28th August 2023. Future correspondence can be addressed to Dr. Hu.

Article link (Advanced Science)