Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.

Conventional anticancer chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, that cooperate for successful tumor eradication. Chemotherapeutic agents stimulate both the innate and adaptive arms of the immune system through several modalities: (i) by promoting specific rearrangements on dying tumor cells, which render them visible to the immune system; (ii) by influencing the homeostasis of the hematopoietic compartment through transient lymphodepletion followed by rebound replenishment of immune cell pools; (iii) by subverting tumor-induced immunosuppressive mechanisms and (iv) by exerting direct or indirect stimulatory effects on immune effectors. Among the indirect ways of immune cell stimulation, some cytotoxic drugs have been shown to induce an immunogenic type of cell death in tumor cells, resulting in the emission of specific signals that trigger phagocytosis of cell debris and promote the maturation of dendritic cells, ultimately resulting in the induction of potent antitumor responses. Here, we provide an extensive overview of the multiple immune-based mechanisms exploited by the most commonly employed cytotoxic drugs, with the final aim of identifying prerequisites for optimal combination with immunotherapy strategies for the development of more effective treatments against cancer.

Type I interferons (IFNs) are cytokines exhibiting antiviral and antitumor effects, including multiple activities on immune cells. However, the importance of these cytokines in the early events leading to the generation of an immune response is still unclear. Here, we have investigated the effects of type I IFNs on freshly isolated granulocyte/macrophage colony-stimulating factor (GM-CSF)–treated human monocytes in terms of dendritic cell (DC) differentiation and activity in vitro and in severe combined immunodeficiency mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID) mice. Type I IFNs induced a surprisingly rapid maturation of monocytes into short-lived tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)–expressing DCs endowed with potent functional activities, superior with respect to the interleukin (IL)-4/GM-CSF treatment, as shown by FACS® analyses, mixed leukocyte reaction assays with allogeneic PBLs, and lymphocyte proliferation responses to HIV-1–pulsed autologous DCs. Type I IFN induced IL-15 production and strongly promoted a T helper cell type 1 response. Notably, injection of IFN-treated HIV-1–pulsed DCs in SCID mice reconstituted with autologous PBLs resulted in the generation of a potent primary immune response, as evaluated by the detection of human antibodies to various HIV-1 antigens. These results provide a rationale for using type I IFNs as vaccine adjuvants and support the concept that a natural alliance between these cytokines and monocytes/DCs represents an important early mechanism for connecting innate and adaptive immunity.

Our results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs.

Interferon (IFN) consensus sequence-binding protein (ICSBP) is a transcription factor playing a critical role in the regulation of lineage commitment, especially in myeloid cell differentiation. In this study, we have characterized the phenotype and activation pattern of subsets of dendritic cells (DCs) in ICSBP−/− mice. Remarkably, the recently identified mouse IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP−/− mice, as revealed by lack of CD11clowB220+Ly6C+CD11b− cells. In parallel, CD11c+ cells isolated from ICSBP−/− spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP−/− mice also displayed a marked reduction of the DC subset expressing the CD8α marker (CD8α+ DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP−/− CD8α+ DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule [ICAM]-1, CD40, CD80, CD86) and of the T cell area-homing chemokine receptor CCR7, whereas they showed higher levels of CCR2 and CCR6, as revealed by reverse transcription PCR. In addition, these cells were unable to undergo full phenotypic activation upon in vitro culture in presence of maturation stimuli such as lipopolysaccharide or poly (I:C), which paralleled with lack of Toll-like receptor (TLR)3 mRNA expression. Finally, cytokine expression pattern was also altered in ICSBP−/− DCs, as they did not express interleukin (IL)-12p40 or IL-15, but they displayed detectable IL-4 mRNA levels. On the whole, these results indicate that ICSBP is a crucial factor in the regulation of two possibly linked processes: (a) the development and activity of mIPCs, whose lack in ICSBP−/− mice may explain their high susceptibility to virus infections; (b) the generation and activation of CD8α+ DCs, whose impairment in ICSBP−/− mice can be responsible for the defective generation of a Th1 type of immune response.