Neoadjuvant In Situ Immunomodulation Enhances Systemic Antitumor Immunity against Highly Metastatic Tumors
Autor: | Fumito Ito, Ryutaro Kajihara, Toshihiro Yokoi, Takaaki Oba, Elizabeth A. Repasky |
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Rok vydání: | 2021 |
Předmět: |
Cancer Research
Lung Neoplasms medicine.medical_treatment Mice Nude Apoptosis Breast Neoplasms CD8-Positive T-Lymphocytes Article B7-H1 Antigen Immunomodulation Mice Breast cancer Immunity Tumor Cells Cultured medicine Animals Humans Immune Checkpoint Inhibitors Mastectomy Cell Proliferation Mice Knockout Mice Inbred BALB C CD40 Radiotherapy biology business.industry Membrane Proteins Dendritic Cells Immunotherapy medicine.disease Combined Modality Therapy Xenograft Model Antitumor Assays Neoadjuvant Therapy Blockade Mice Inbred C57BL Repressor Proteins Radiation therapy Regimen Basic-Leucine Zipper Transcription Factors Oncology biology.protein Cancer research Female business CD8 |
Zdroj: | Cancer Res |
ISSN: | 1538-7445 0008-5472 |
Popis: | Neoadjuvant immunotherapy, given before surgical resection, is a promising approach to develop systemic antitumor immunity for the treatment of high-risk resectable disease. Here, using syngeneic and orthotopic mouse models of triple-negative breast cancer, we have tested the hypothesis that generation of tumor-specific T-cell responses by induction and activation of tumor-residing Batf3-dependent conventional type 1 dendritic cells (cDC1) before resection improves control of distant metastatic disease and survival. Mice bearing highly metastatic orthotopic tumors were treated with a combinatorial in situ immunomodulation (ISIM) regimen comprised of intratumoral administration of Flt3L, local radiotherapy, and in situ TLR3/CD40 stimulations, followed by surgical resection. Neoadjuvant ISIM (neo-ISIM) generated tumor-specific CD8+ T cells that infiltrated into distant nonirradiated metastatic sites, which delayed the progression of lung metastases and improved survival after the resection of primary tumors. The efficacy of neo-ISIM was dependent on de novo adaptive T-cell immunity elicited by Batf3-dependent dendritic cells and was enhanced by increasing dose and fractionation of radiotherapy, and early surgical resection after the completion of neo-ISIM. Importantly, neo-ISIM synergized with programmed cell death protein-1 ligand-1 (PD-L1) blockade to improve control of distant metastases and prolong survival, while removal of tumor-draining lymph nodes abrogated the antimetastatic efficacy of neo-ISIM. Our findings illustrate the therapeutic potential of neoadjuvant multimodal intralesional therapy for the treatment of resectable tumors with high risk of relapse. Significance: Neoadjuvant induction and activation of cDC1s in primary tumors enhances systemic antitumor immunity, suppresses metastatic progression, improves survival, and synergizes with anti–PD-L1 therapy. |
Databáze: | OpenAIRE |
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