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Tumor specimens from patients in a trial of cisplatin-based adjuvant chemotherapy for non–small-cell lung cancer were analyzed for the presence of ERCC1, an enzyme that participates in the repair of DNA damage caused by cisplatin. The absence of ERCC1 in the tumor was associated with a survival benefit from cisplatin-based adjuvant chemotherapy, whereas patients whose tumor expressed the enzyme failed to benefit from the chemotherapy. The absence of ERCC1 in the tumor was associated with a survival benefit from cisplatin-based adjuvant chemotherapy, whereas patients whose tumor expressed the enzyme failed to benefit from the chemotherapy. Lung cancer is a leading cause of death from cancer in most industrialized countries. 1 Despite undergoing complete resection of non–small-cell lung cancer, 33% of patients with pathological stage IA die within 5 years, as do 77% of those with pathological stage IIIA. 2 Clinical trials have tested the ability of adjuvant chemotherapy to improve survival after complete resection of non–small-cell lung cancer. The International Adjuvant Lung Cancer Trial (IALT) demonstrated an absolute benefit of 4.1% in 5-year overall survival among 1867 patients who were treated with adjuvant cisplatin-based chemotherapy. 3 Several other randomized studies have confirmed the benefit of postoperative platinum-based therapy . . .

Cytotoxic T lymphocytes and natural killer cells are essential effectors of anti-tumor immune responses in vivo . Dendritic cells (DC) 'prime' tumor antigen-specific cytotoxic T lymphocytes; thus, we investigated whether DC might also trigger the innate, NK cell-mediated anti-tumor immunity. In mice with MHC class I-negative tumors, adoptively transferred- or Flt3 ligand-expanded DC promoted NK cell-dependent anti-tumor effects. In vitro studies demonstrated a cell-to-cell contact between DC and resting NK cells that resulted in a substantial increase in both NK cell cytolytic activity and IFN-γ production. Thus, DC are involved in the interaction between innate and adaptive immune responses.

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

Metastatic renal-cell carcinoma is refractory to chemotherapy, and median survival is usually less than a year. 1 – 4 Performance status, number of metastatic sites, time from diagnosis of the primary tumor to the discovery of metastases, and weight loss are important prognostic factors. 1 , 5 , 6 In 1985 and 1987, Rosenberg et al. 7 , 8 reported that recombinant human interleukin-2 (aldesleukin) caused dramatic shrinkage of tumors, particularly in patients with metastatic renal-cell carcinoma. These results sparked the development of cytokine treatment in oncology. The pronounced toxic effects described in the initial reports from trials involving a high-dose bolus of interleukin-2 prompted the development . . .

Cancer treatment is slowly shifting from an approach in which the tissue of origin and the histology were the guiding principles for the choice of chemotherapy towards a genotype-centric approach in which the changes in the cancer genome are used to select patients for treatment with highly selective and targeted drugs. This transition has all the hallmarks of a disruptive innovation and requires major adjustments in the way that cancer is diagnosed and treated. We discuss here the hurdles on the road ahead to a more personalized treatment of cancer. •Tissue preservation must be adapted to optimize cancer genotyping.•Cancer care must be concentrated in regional centers of excellence.•Clinical testing of drugs in large phase III trials will become obsolete.•Early detection through “liquid biopsies” can improve survival.

Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Rα- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1+ cells. In humans, Dex express functional IL-15Rα which allow proliferation and IFNγ secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo.

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Ralpha- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1(+) cells. In humans, Dex express functional IL-15Ralpha which allow proliferation and IFNgamma secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo.

The interferon (IFN)-γ–induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice 1 , 2 . Here we show that the main source of IFN-γ is not the conventional NK cell but a subset of B220 + Ly6C − dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220 + NK1.1 + dendritic cells secrete high levels of IFN-γ and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2 −/− Il2rg −/− mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.

The initiation of T-cell–mediated antitumor immune responses requires the uptake and processing of tumor antigens by dendritic cells and their presentation on MHC-I molecules. Here we show in a human in vitro model system that exosomes, a population of small membrane vesicles secreted by living tumor cells, contain and transfer tumor antigens to dendritic cells. After mouse tumor exosome uptake, dendritic cells induce potent CD8 + T-cell–dependent antitumor effects on syngeneic and allogeneic established mouse tumors. Therefore, exosomes represent a novel source of tumor-rejection antigens for T-cell cross priming, relevant for immunointerventions.