Systemically inducing trained immunity overcomes solid tumors' immunosuppressive microenvironment.

Abstract

Hematopoietic bone marrow progenitors are increasingly implicated as an origin of immunosuppression in cancer. We have previously shown that trained immunity induction using nanomedicine potentiates checkpoint blockade therapy. Here, we studied how this approach's induction of trained immunity systemically overcomes the immunosuppressive tumor microenvironment. We found changes in the tumor microenvironment to mirror functional changes in the hematopoietic system in a melanoma mouse model. Single cell sequencing methods disclosed a shift in the tumor-associated macrophage population from immunosuppressive to antitumorigenic. Uniquely, a trained immunity and checkpoint blockade combination therapy mobilized natural killer cells which, in conjunction with the functional changes in the myeloid cell compartment, effectively activated T cells. Last, we established the effectiveness of our approach in mouse models of breast, lung, and pancreatic cancer. Collectively, our data show that the systemic induction of trained immunity rebalances the immune system for effective checkpoint blockade therapy.