Hematopoietic stem cell encoded anti-tumor immunity: mechanisms and function - ABSTRACT Intravesical administration of bacillus Calmette-Guérin (BCG), the first immunotherapy and the only bacterial therapy of cancer, is the most effective treatment for non–muscle invasive bladder cancer (NMIBC), but cancer recurs in approximately 50% of treated patients, many of whom require major surgery and are at risk for metastatic disease. Despite substantial efforts, there are no reliable pretreatment predictors of BCG response, partially due to an incomplete understanding of BCG’s mechanism of action. We discovered that BCG-induced tumor elimination in mice is due to induction of long-term T cell immunity to tumor antigens, and there is evidence that this mechanism plays a role in the efficacy of BCG in treating human disease as well. However, the upstream events stimulated by BCG that ultimately lead to tumor-specific T cell immunity are unknown. It is now recognized that certain stimuli, including BCG, lead to epigenetic changes in hematopoietic stem and progenitor cells (HSPCs) that can confer differentiation bias (eg, increased myeloid and granulocyte output) and the acquisition of epigenetic programs in mature progeny cells, resulting in an adapted capacity of innate immune cells, particularly macrophages and dendritic cells, to react to restimulation (termed innate immune memory). Although there is emerging evidence that the innate immune memory stimulated by BCG can provide heterologous immunity against viral infection, its role in the antitumor effects of BCG is relatively unexplored. Our recently published data in mice demonstrate that intravesical BCG can traffic to the bone marrow, where it alters the phenotypic and epigenetic state of centrally positioned bone marrow HSPCs through interferon gamma. Human bladder cancer patients receiving intravesical BCG have strong evidence of HSPC remodeling through the same IFN gamma stimulated pathways. Reconstitution of the hematopoietic compartment of irradiated mice with Lin-Sca1+c-Kit+ (LSK) HSPCs from BCG-treated mice inhibits tumor growth, enhances myeloid cell infiltration of the tumor, reprograms tumor infiltrating neutrophils, and synergizes with PD1 blockade, demonstrating that HSPC-derived innate immune cells reprogram the myeloid tumor microenvironment and enhance T cell mediated anti-tumor immunity. This proposal will elucidate the IFN dependent mechanisms by which BCG stimulates HSPC reprogramming, the innate immune mechanisms by which HSPC encoded anti-tumor immunity eliminates tumors, and will determine whether measurement of HSPC encoded myeloid reprogramming, detected in peripheral blood, can predict BCG response in NMIBC patients. These studies use complex immunologic models, including bone marrow transplantation, in vertebrate animals as these mechanistic studies are not possible in surrogate model systems. If successful, these studies will provide new mechanistic insights into the oldest immunotherapy of cancer, identify candidate biomarkers to predict the success of this specific therapy for bladder cancer, and give a deeper understanding of how HSPC encoded myeloid reprogramming can be applied to immunotherapy of a wider range of cancers.
