Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity

• DOI: 10.1136/jitc-2021-002408
• Publication Date: 2021-09-16T16:47:22Z
• Authors: Clément Anfray; Francesco Mainini; Elisabeth Digifico; Akihiro Maeda; Marina Sironi; Marco Erreni; Achille Anselmo; Aldo Ummarino; Sara Gandoy; Francisco Expósito; Miriam Redrado; Diego Serrano; Alfonso Calvo; Marvin Martens; Susana Bravo; Alberto Mantovani; Paola Allavena; Fernando Torres A...
• Keywords: 0301 basic medicine; lung neoplasms; Antiviral Agents; ACTIVATION; Mice; 03 medical and health sciences; Lung neoplasms; Cell Line, Tumor; Neoplasms; Tumor-Associated Macrophages; innate; Innate; Animals; Humans; IMMUNOTHERAPY; RC254-282; Macrophages; Immunity; Imidazoles; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Drug Synergism; immunity; Combined Modality Therapy; macrophages; 3. Good health; Oncolytic and Local Immunotherapy; Poly I-C; METASTASIS; immunotherapy; Immunotherapy

Background Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of immune system to fight cancer and hinder antitumoral efficacy most treatments currently applied in clinic. Previous studies have evaluated response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) monotherapies; however, their combination for treatment has not been explored. This study investigates macrophage reprogramming poly(I:C) combined with R848 R837, versus single treatments. Methods TLR agonist were vitro toxicity immunostimulatory activity Alamar Blue, ELISA flow cytometry using primary human murine M-CSF-differentiated macrophages. Cytotoxic TLR-treated toward cells was an functional assay cytometry. For vivo experiments, CMT167 lung model MN/MCA1 fibrosarcoma metastasizing lungs used; tumor-infiltrating leukocytes cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic protein–protein interaction analysis. Results demonstrated higher R837 polarize M1-like antitumor effectors vitro. In vivo, intratumoral synergistic poly(I:C)+R848 significantly prevented tumor growth metastasis immunocompetent models. Regressing tumors showed increased infiltration M1:M2 ratio, recruitment CD4 + CD8 T cells, accompanied reduction CD206 TAMs FOXP3 /CD4 cells. The depletion both resulted complete loss efficacy. Treated mice acquired systemic resistance rechallenge mediated boosted cytotoxic T-cell proliferation. Proteomic experiments validate superior activation innate immunity poly(I:C)+R837, protein–protein-interaction network analysis reveal STAT1 pathway. Discussion These findings demonstrate responses on local administration support application this therapy patients solid