Combination treatment with immunogenic and anti-PD-L1 polymer-drug conjugates of advanced tumors in a transgenic MMTV-PyMT mouse model of breast cancer

Immune checkpoint blockade has revolutionized the treatment of tumors with immunogenic microenvironments. However, low response rate and acquired resistance are still major challenges. Herein we used a more clinically relevant model of transgenic MMTV-PyMT tumor that more closely mimics the development of human breast cancer in an immunocompetent background to investigate a polymer-based chemo-immunotherapy. We have found that tumors acquired an increased degree of immune suppression during progression, rendering them unresponsive to anti-PD-L1 therapy. To treat large tumors at their advanced stage, we applied a combination strategy consisting of two polymer-drug conjugates that could induce immunogenic cell death (ICD) and disrupt the PD-L1/PD-1 interaction, respectively. Although ICD-inducing conjugate remodeled tumor immune microenvironment by facilitating significant CD8⁺ T cell infiltration, advanced tumor adapted the immune suppressive mechanism of elevating PD-L1 expression on both cancer cells and myeloid cells thereafter to enable continued tumor growth. Concurrent treatment of PD-L1 blocking conjugate not only abrogated the PD-L1 expression from the two disparate cellular sources, but also considerably reduced the number of immunosuppressive myeloid cells, thereby leading to a significant shrinkage of advanced tumors. Our data provide evidence that combinatory strategy of ICD–inducing and PD-L–blocking modalities could reverse immune suppression and establish a basis for the rational design of cancer immunotherapy.