The contribution of hematopoietic stem and progenitor cells to tumor progression and metastasis

Cancer resistance and spread are some of the major causes of death in cancer patients. Recent studies demonstrated that immune cell myeloid skewing is a prominent promoter of metastasis and resistance to immunotherapy, therefore, serving as a critical step in dictating tumor fate. We have previously shown that following immunotherapy, the host generates pro-tumorigenic activities which contribute to tumor regrowth and metastasis spread. We found that hematopoietic stem and progenitor cells (HSPCs) and their early progenitor subsets are substantially increased in tumors bearing aggressive phenotype of those that underwent immunotherapy. In an experimental cell tracking system, we found that these HSPCs specifically differentiate into monocyte-dendritic progenitors (MDPs) that further differentiate into immunosuppressive macrophages. These activities can explain tumor spread and resistance to immunotherapy. In my presentation I will discuss the major factors which contribute to MDP differentiation fate. I will show how upregulation of IL-6 induced in response to immunotherapy or in mice bearing highly metastatic tumors contributes to HSPC differentiation into immunosuppressive myeloid progeny. In this regard, mice bearing resistant tumors to immunotherapy display lower number of MDPs but higher number of their differentiated immunosuppressive cells when compared to tumor sensitive to immunotherapy. Consequently, blocking IL-6 in combination with immunotherapy resulted in decreased number of MDPs and an increase in immunotherapy outcomes. Our study reveals a unique crosstalk between tumor cells and HSPCs at the tumor microenvironment which contributes not only to an aggressive tumor phenotype but also can explain resistance to immunotherapy, and ways to overcome it.