| dc.description.abstract | Solid tumors are infiltrated by non-malignant cells that actively shape cancer growth. These include immune cells, which are comprised of various lymphoid and myeloid cell subsets displaying diverse tumor-regulatory functions. In the past decade, targeting the immune system has been validated as an effective strategy to treat cancer, as therapeutically manipulating certain immune cells, such as T lymphocytes, can durably control cancer progression in some patients. Despite these remarkable advances in cancer therapy, our mechanistic understanding of tumor-immune interactions remains incomplete. For example, cancer-exerted effects on host responses beyond the local tumor microenvironment are less studied, but could be highly relevant since tumor-infiltrating immune cells are dynamically replenished by bone marrow-derived cells. Additionally, which, and how, immune cell subsets control tumor progression, and to what extent these processes are perturbed by (and can be harnessed for) anticancer therapies, require clarification. Addressing these types of questions could not only expand our fundamental knowledge of tumor progression, but also have far-reaching consequences by offering new therapeutic avenues.
With these ultimate goals in mind, we have begun to interrogate various aspects of tumor-immune interactions using pre-clinical tumor models. We focused on lung cancer, as it remains the number one cause of cancer-related deaths worldwide and many patients lack effective treatments. First, we investigated long-range interactions between lung tumors and the bone. Our findings newly link bone marrow stromal cells to distant tumor outgrowth via the production of cancer-promoting myeloid cells. Second, we asked whether selecting chemotherapeutic drugs to exploit their immune stimulatory capacities could generate a T cell rich tumor stroma amenable to immunotherapy targeting. Here, we identified a drug combination that controls cancer growth, stimulates tumor T cell infiltration, and sensitizes tumors to checkpoint blockade therapy. Third, we comprehensively mapped tumor-infiltrating immune cell transcriptomes on a single cell level to reveal previously unappreciated cancer- and immunotherapy-induced myeloid cell substates in the lung.
Combined, we provide new insight into local and systemic tumor-host interactions and drug effects on tumor microenvironments, which could be harnessed for clinical translation. | |
