Inflammatory and immune reactions in response to chemotherapy-induced cell death

Abstract

Successful chemotherapy accounts for both tumor-related factors and host immune response. Compelling evidence suggests that some chemotherapeutic agents can and do induce an immunogenic type of cell death stimulating tumor-specific immunity. My PhD Thesis work shows 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 CD8 α+ 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 tumor antigen cross-presentation and T-cell cross-priming, resulting in the induction of a strong antitumor response and tumor rejection. The above mentioned, newly described, effects strongly support the observed powerful capability of CTX and type I IFN to synergize in the induction of antitumor responses in vivo. This study provide new knowledge on type IFN I and CTX, old molecules whose newly described properties can be exploited for the design of innovative clinical protocols in which the generation of effective antitumor immunity is crucially required.