{
  "abstract": "Background Immune exclusion inhibits antitumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC.Methods We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-naïve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of trophoblast cell-surface antigen 2 (TROP2), a key target of anticancer antibody drug conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-programmed cell death protein 1 (PD-1) therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings.Results We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T-cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T-cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC sacituzumab govitecan, enhances the anti-PD-1 response and improves T-cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD-1 therapy in human breast cancer.Conclusions This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed therapy to activate antitumor immunity and enhance immunotherapy response.",
  "authors": [
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA",
        "Department of Immunology, Mayo Clinic Arizona, Phoenix, Arizona, USA"
      ],
      "name": "Bogang Wu"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA",
        "Department of Immunology, Mayo Clinic Arizona, Phoenix, Arizona, USA"
      ],
      "name": "Win Thant"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Elena Bitman"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Ting Liu"
    },
    {
      "affiliations": [
        "Department of Immunology, Mayo Clinic Arizona, Phoenix, Arizona, USA",
        "Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Jie Liu"
    },
    {
      "affiliations": [
        "Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Eleftherios I Paschalis"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Bidish K Patel"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Cole Nawrocki"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Katherine H Xu"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Linda T Nieman"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "David T Ting"
    },
    {
      "affiliations": [
        "Department of Immunology, Mayo Clinic Arizona, Phoenix, Arizona, USA"
      ],
      "name": "Bruna de Gois Macedo"
    },
    {
      "affiliations": [
        "Department of Immunology, Mayo Clinic Arizona, Phoenix, Arizona, USA"
      ],
      "name": "Yang Cheng"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Kevin Jiang"
    },
    {
      "affiliations": [
        "Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Fengfei Sun"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Nayana Thimmiah"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Sheng Sun"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Rachel O Abelman"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Veerle I Bossuyt"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Steven J Isakoff"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Laura M Spring"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA"
      ],
      "name": "Aditya Bardia"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA",
        "Ludwig Center at Harvard, Boston, Massachusetts, USA"
      ],
      "name": "Leif W Ellisen"
    }
  ],
  "title": "TROP2/claudin program mediates immune exclusion to impede checkpoint blockade in breast cancer",
  "uid": "e6ab7b42-a9d8-5ab3-a8b4-a290f36487a8"
}