Effects of metronomic chemotherapy on immunity

Abstract

Chemotherapeutic agents are widely used for cancer treatment. However, these agents have the potential to kill tumor cells as well as nontumor cells, including immune cells. Therefore, conventional and maximum-tolerated dose chemotherapy is inevitably associated with the risk of immunity deterioration. Metronomic chemotherapy is a unique protocol that administers chemotherapeutic agents at relatively low doses, without prolonged drug-free periods. Metronomic chemotherapy was primarily developed to target circulating endothelial progenitor cells to inhibit tumor angiogenesis. Alternatively, certain chemotherapeutic agents have immunostimulatory effects. Specifically, cyclophosphamide (CTX) and gemcitabine (GEM) administration can decrease two major immunosuppressive cells, regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), respectively, both of which increase in tumor-bearing hosts. However, administration protocols heavily influence the host's immunity because chemotherapeutic agents potentially kill proliferating lymphocytes. To this end, we investigated the effects of a CTX administration protocol on the in vivo induction of antitumor T cells in a preclinical model. We found that CTX administration at 4-day intervals deteriorated antitumor T cell immunity. Given these findings, we further tested a combination chemotherapy protocol with CTX and GEM at 8-day intervals and found that without impairing immunological competence, this protocol elicited antitumor T cells by decreasing Treg cells and MDSCs. In this chapter, I outline the in vivo induction of antitumor T cell immunity after chemotherapy, review the effects of metronomic chemotherapy on immunity, and discuss its underlying mechanisms.