Oleuropein reprograms the immunosuppressive footprint of tumor-associated myeloid cells and enhances PD-L1/PD-1 blockade immunotherapy in cancer

Therapies based on PD-1/PD-L1 blockade fail in most cancer patients. Here we evaluated the capacities of oleuropein to reprogram tumor-associated immunosuppressive myeloid cells to increase the potency of immunotherapies. Oleuropein caused major global reprogramming of monocytic and granulocytic myeloid-derived suppressor cells and tumor-associated macrophages towards immunostimulatory subsets. Differential quantitative proteomics uncovered activated and down-modulated pathways at high resolution for each subset which regulated major differentiation programs. Oleuropein significantly potentiated the capacities of myeloid cells to activate T-cells and enhanced antitumor properties of PD-1 blockade, either by systemic anti-PD-1 antibody administration, or locally by intratumor antibody delivery with a self-amplifying RNA vector based on Semliki Forest virus. Combination therapies decreased tumor infiltration by immunosuppressive myeloid cells and increased dendritic cell recruitment within draining lymph nodes, leading to systemic antitumor T-cell responses. Potent therapeutic activities were evident in lung cancer models resistant to immunotherapies and in colon cancer models.