Oleuropein-driven reprogramming of the myeloid cell compartment to sensitise tumours to PD-1/PD-L1 blockade strategies

• Published in: British journal of cancer Vol. 130; no. 5; pp. 869 - 879
• Main Authors: Blanco, Ester, Silva-Pilipich, Noelia, Bocanegra, Ana, Chocarro, Luisa, Procopio, Antonio, Ausín, Karina, Fernandez-Irigoyen, Joaquín, Fernández, Leticia, Razquin, Nerea, Igea, Ana, Garnica, Maider, Echaide, Miriam, Arasanz, Hugo, Vera, Ruth, Escors, David, Smerdou, Cristian, Kochan, Grazyna
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.03.2024; Nature Publishing Group
• Subjects: 692/4017; 692/4028/67/1059/2325; Antibodies; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Cancer immunotherapy; Cancer Research; Cell differentiation; Colon cancer; Colorectal carcinoma; Dendritic cells; Drug Resistance; Epidemiology; Immunomodulation; Immunostimulation; Immunotherapy; Lung cancer; Lymph nodes; Lymphocytes T; Macrophages; Metastases; Molecular Medicine; Monocytes; Myeloid cells; Oncology; PD-1 protein; PD-L1 protein; Proteomics; Suppressor cells; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-023-02561-y

Background Previous studies have shown that functional systemic immunity is required for the efficacy of PD-1/PD-L1 blockade immunotherapies in cancer. Hence, systemic reprogramming of immunosuppressive dysfunctional myeloid cells could overcome resistance to cancer immunotherapy. Methods Reprogramming of tumour-associated myeloid cells with oleuropein was studied by quantitative differential proteomics, phenotypic and functional assays in mice and lung cancer patients. Combinations of oleuropein and two different delivery methods of anti-PD-1 antibodies were tested in colorectal cancer tumour models and in immunotherapy-resistant lung cancer models. Results Oleuropein treatment reprogrammed monocytic and granulocytic myeloid-derived suppressor cells, and tumour-associated macrophages towards differentiation of immunostimulatory subsets. Oleuropein regulated major differentiation programmes associated to immune modulation in myeloid cells, which potentiated T cell responses and PD-1 blockade. PD-1 antibodies were delivered by two different strategies, either systemically or expressed within tumours using a self-amplifying RNA vector. Combination anti-PD-1 therapies with oleuropein increased tumour infiltration by immunostimulatory dendritic cells in draining lymph nodes, leading to systemic antitumour T cell responses. Potent therapeutic activities were achieved in colon cancer and lung cancer models resistant to immunotherapies, even leading to complete tumour regression. Discussion Oleuropein significantly improves the outcome of PD-1/PD-L1 blockade immunotherapy strategies by reprogramming myeloid cells.