{
  "abstract": "Background Butyrophilin 1A1 (BTN1A1) has recently emerged as a novel immune checkpoint molecule that suppresses T-cell activation through mechanisms largely independent of the canonical PD-1/PD-L1 pathway. Its expression is minimal under physiological conditions but is upregulated in tumor cells under stress, particularly following cytotoxic insults. As such, BTN1A1 represents a promising immunotherapeutic target, especially in the context of PD-L1-low or immune-cold tumors, where conventional checkpoint inhibitors often fail. Chemotherapy, particularly agents like Docetaxel, can induce immunogenic cell death (ICD) and upregulate immune-modulatory molecules. Based on this, we hypothesized that blockade of BTN1A1 using a humanized monoclonal antibody, hSTC810 (Nelmastobart), in combination with Docetaxel, could enhance anti-tumor immunity through complementary mechanisms. This study aimed to evaluate the therapeutic synergy between hSTC810 and Docetaxel in non-small cell lung cancer (NSCLC) using three distinct and complementary preclinical models.Methods A549 NSCLC cells and patient-derived lung cancer organoids were transfected to express red fluorescent protein (RFP) for real-time visualization and quantification of tumor growth. Experimental treatments included human PBMCs, hSTC810, and Docetaxel administered alone or in combination. Tumor growth inhibition was assessed in 3D A549 spheroids and organoids based on RFP signal intensity and area. For in vivo evaluation, RFP-labeled A549 cells were co-injected with PBMCs and hSTC810 into the yolk sac of zebrafish embryos, followed by systemic treatment with Docetaxel. Tumor burden was quantified using fluorescence microscopy, and embryo development was monitored for signs of toxicity.Results Docetaxel treatment increased BTN1A1 expression on both A549 cells and lung organoids, supporting its classification as a stress-induced immune checkpoint. In 3D co-culture systems, Docetaxel alone modestly reduced tumor growth, while the addition of PBMCs enhanced cytotoxicity. The most significant anti-tumor effect was observed with the triple combination of PBMC + Docetaxel + hSTC810, which markedly outperformed combinations involving atezolizumab. In the organoid model, hSTC810 restored T cell-mediated tumor killing, further validating BTN1A1’s immunosuppressive role. In zebrafish xenografts, hSTC810 + Docetaxel produced the greatest tumor regression without inducing observable toxicity or developmental delay.Conclusions Across three physiologically relevant NSCLC models, hSTC810 synergized with Docetaxel to suppress tumor growth by enhancing immune-mediated cytotoxicity. These findings support BTN1A1 as a viable immunotherapeutic target and justify clinical development of hSTC810 in combination with chemotherapy, particularly for patients with PD-L1-refractory or immune-desert NSCLC.",
  "authors": [
    {
      "affiliations": [
        "STCube Pharmaceuticals, Inc, Rockville, MD, USA"
      ],
      "name": "Seung-Hoon Lee"
    },
    {
      "affiliations": [
        "STCube Pharmaceuticals, Inc, Rockville, MD, USA"
      ],
      "name": "Young-Seung Kim"
    },
    {
      "affiliations": [
        "STCube Pharmaceuticals, Inc, Rockville, MD, USA"
      ],
      "name": "Chunai Wu"
    },
    {
      "affiliations": [
        "STCube Pharmaceuticals, Inc, Rockville, MD, USA"
      ],
      "name": "Bong-Ki Hong"
    },
    {
      "affiliations": [
        "STCube Pharmaceuticals, Inc, Rockville, MD, USA"
      ],
      "name": "Andrew H Park"
    },
    {
      "affiliations": [
        "STCube, Inc, Seoul, Republic of Korea"
      ],
      "name": "Hyunjin Jung"
    },
    {
      "affiliations": [
        "STCube Pharmaceuticals, Inc, Rockville, MD, USA",
        "STCube, Inc, Seoul, Republic of Korea"
      ],
      "name": "Stephen S Yoo"
    }
  ],
  "title": "410 BTN1A1 blockade enhances chemotherapy-induced anti-tumor immunity in preclinical lung cancer models",
  "uid": "0ba7671f-d0e4-5dab-9544-e70bbdbbc40f"
}