Abstract
Successful chemotherapy accounts for both tumor-related factors and host immune response. Compelling evidence suggests that some chemotherapeutic agents can induce an immunogenic type of cell death stimulating tumor-specific immunity. Here, we show that cyclophosphamide (CTX) exerts two types of actions relevant for the induction of antitumor immunity in vivo: (i) effect on dendritic cell (DC) homeostasis, mediated by endogenous type I interferons (IFN-I), leading to the preferential expansion of CD8α(+) DC, the main subset involved in the cross-presentation of cell-derived antigens; and (ii) induction of tumor cell death with clear-cut immunogenic features capable of stimulating tumor infiltration, engulfment of tumor apoptotic material, and CD8 T-cell cross-priming by CD8α(+) DC. Notably, the antitumor effects of CTX were efficiently amplified by IFN-I, the former providing a source of antigen and a "resetting" of the DC compartment and the latter supplying optimal costimulation for T-cell cross-priming, resulting in the induction of a strong antitumor response and tumor rejection. These results disclose new perspectives for the development of targeted and more effective chemoimmunotherapy treatments of cancer patients.
Highlights
Many clinical studies based on the combination of chemotherapy and immunotherapy have been published over the past years showing variable responses [1]
Recent evidence suggest that some anticancer drugs, such as anthracyclines, induce an immunogenic type of apoptosis that stimulates the engulfment of apoptotic bodies by dendritic cells (DC) and the activation of cytotoxic CD8 T cells through a process known as "cross-priming" [6]
Previous work suggests that CTX may condition DC homeostasis [16, 17], the exact mechanisms of Bone marrow (BM)
Summary
Many clinical studies based on the combination of chemotherapy and immunotherapy have been published over the past years showing variable responses [1]. Recent evidence suggest that some anticancer drugs, such as anthracyclines, induce an immunogenic type of apoptosis that stimulates the engulfment of apoptotic bodies by dendritic cells (DC) and the activation of cytotoxic CD8 T cells through a process known as "cross-priming" [6]. Among cytokines induced by CTX, type I interferons (IFN-I) mediate many of the effects ascribed to the drug, including the expansion of memory T lymphocytes [12] and the activation of CD11bþ myeloid cells [13]. CTX induces an immunogenic tumor apoptosis, characterized by sCRT exposure and release of soluble factors, among which HMGB1, capable of activating CD8aþ DC, efficiently takes up tumor apoptotic cells and cross-present the EG7-derived OVA both in vitro and at the tumor site. We show that CD8 T-cell crosspriming by DC and CTX-induced antitumor effect in vivo can be strongly enhanced by IFN-I
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
