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Abstract Non-small cell lung cancer (NSCLC) and head and neck cancer (HNC), ranking respectively as a leading cause of cancer-related death and the sixth most common cancer worldwide. Despite treatment advancements, there's a pressing need for more effective strategies to improve survival and quality of life for NSCLC and HNC patients. Carolyn Bertozzi group recently reported in Nature the groundbreaking protein degraders named lysosome-targeted chimeras (LYTACs), which have bispecific binding affinity that drives cell-surface endocytic receptors to drag membrane or extracellular oncogenic proteins to lysosomes for degradation. They have successfully targeted critical oncoproteins such as epidermal growth factor receptor (EGFR) and more. However, current degradation demonstration was limited to in vitro cancer cells, LYTACs' impact on immune cell modulation and their therapeutic potentials in preclinical animal models remain unknown and require extensive evaluation before venturing to clinical trials. Our group and others have identified galectin-1 (Gal-1) as a multifaceted immunosuppressive biomarker overexpressed in NSCLC and HNC. By interacting with glycosylated receptors (e. g. CD45) on immune cells, it results in apoptosis of cytotoxic T cells, expansion of regulatory T cells, and intratumoral recruitment of myeloid-derived suppressor cells. Despite promising as an immune checkpoint target, effective anti-Gal-1 therapies are currently absent in clinical trials. Through histopathological analyses, we have confirmed substantial LYTAC receptor (cation-independent mannose-6-phosphate receptor, CI-M6PR) expression in ~200 HNC and ~400 NSCLC patient samples. Collaborating with Bertozzi group, we have developed the first Gal-1 targeting LYTAC named G-M6Pn which triggers significant target protein degradation in various human HNC and NSCLC cell lines. Such efficient Gal-1 degradation leads to significant immunosuppression reversal by stimulating CD8+ T cell and natural killer (NK) cell activation while dampening regulatory T cell (Treg) activity in both cell experiments and humanized mouse tumor models, resulting in excellent tumor/metastases control and survival improvement on both NSCLC and HNC models. When synergized with stereotactic ablative radiotherapy, the antitumor immune responses are further amplified and G-M6Pn also mediates ‘abscopal effect’ inhibiting non-irradiated tumors. This study thus contributes to expediting clinical translation of LYTACs as novel immune checkpoint degraders to improve personalized radio-immunotherapy of cancer. Citation Format: Yuyan Jiang, Green Ahn, Mobeen Rahman, Hongbin Cao, Carolyn Bertozzi, Qunh Le. LYTAC targeting galectin-1 to enhance radioimmunotherapy of cancers in the upper aerodigestive tract abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3880.
Jiang et al. (Fri,) studied this question.