BTN1A1-targeted immunotherapy enhances standard treatment efficacy in NSCLC and colorectal cancer: Insights from patient-derived organoids and zebrafish models

초록

Background: Non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) are characterized by high intratumoral heterogeneity and frequent resistance to standard therapies. BTN1A1, a novel immune checkpoint molecule, is predominantly expressed in chemo-resistant tumor subsets and exhibits mutually exclusive expression with PD-L1. This study evaluated the therapeutic potential of targeting BTN1A1 with the monoclonal antibody hSTC810 in combination with standard chemotherapy and PD-L1 blockade using patient-derived organoids (PDOs) and zebrafish xenograft models. Methods: PDOs were generated from NSCLC and CRC tumor tissues and cultured in Matrigel. Treatment regimens included hSTC810 and anti–PD-L1 antibodies, administered alone or with chemotherapy (docetaxel for NSCLC; FOLFOX/FOLFIRI for CRC). T cell co-culture assays and immunofluorescence imaging were used to assess immune activation, viability, and apoptosis. In vivo validation was performed using zebrafish xenograft models injected with labeled tumor cells, hPBMCs, and treatment agents. Results: BTN1A1 expression was upregulated following chemotherapy in both NSCLC and CRC PDOs. hSTC810 significantly enhanced T cell–mediated tumor cell killing and induced apoptosis in PDOs. Combination therapy with hSTC810 and chemotherapy demonstrated superior efficacy compared to monotherapy. In zebrafish models, anti-BTN1A1 therapy synergized with docetaxel and PD-L1 blockade, resulting in reduced tumor burden and increased immune infiltration. These effects were particularly notable in PD-L1–negative tumor subsets, where BTN1A1 was enriched. Conclusions: Targeting BTN1A1 with hSTC810 enhances the anti-tumor efficacy of standard chemotherapy and immune checkpoint blockade in NSCLC and CRC models. Our data support BTN1A1 as a promising therapeutic target for PD-L1–negative or chemo-resistant tumors and highlight the utility of PDOs and zebrafish models for translational immunotherapy research.