Many human cancers fail to respond to chemotherapy, and cancers that initially respond frequently acquire drug resistance and relapse. This process of tumor relapse is particularly confounding, as patients can be in remission for years following treatment prior to the reemergence of a cancer. Additionally, tumors that relapse have generally acquired resistance to the initial treatment. While conventional anti-cancer therapies have been in clinical use for decades, little is known about the mechanisms by which a tumor cell can survive treatment and persist in a patient for extended period of time. In fact, a major cause of cancer deaths is the inability to eradicate small sets of surviving tumor cells, termed “minimal residual disease” or “MRD”. Work from our laboratory has found that chemotherapy paradoxically elicits a pro-survival response in certain anatomical cites1-3. Specifically, normal cells proximal to tumor cells secrete factors that counter the effects of the chemotherapy. This survival response likely serves to protect normal progenitor and stem cells to allow for tissue regeneration following damage4, but it is coopted by tumor cells that find themselves in these specialized sites.
In addition to conventional chemotherapy, we have recently shown that select microenvironments can underlie resistance to antibody-based therapy5. Using a humanized model of treatment-refractory B-cell leukemia, we have identified the bone marrow as a site of persistent MRD. Specifically, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy.
These data suggest that effective cancer therapy may not only involve targeting cancer cells but also may require inhibiting survival signals emanating from surrounding cells. By generating multiple models of MRD, we have not only identified mechanisms of tumor cell persistance, but also strategies to sensitize chemorefractory tumors to both front-line and targeted schemotherapy.