Chemosensitization strategies for the treatment of lung cancer.

In spite of major research efforts, the treatment of advanced non-small cell lung cancer is still largely inefficient. Indeed, this cancer type has a poor prognosis, and no curative therapies are available. Over the last years, it has been become increasingly clear that (relatively) successful chemotherapies such as the anthracycline-based neoadjuvant treatment of locally advanced breast cancer are largely influenced by the immunosurveillance system. Thus, the pre-treatment composition of the immune infiltrate of mammary carcinomas determined by microarray analyses clearly affects the probability of successful therapy. A CXCL13centered metagene signature reflecting the intratumoral presence of interferon-γ-producing T cells has a positive predictive impact, indicating that the pre-existing anticancer immune response influences therapeutic outcome [1]. In addition, changes in the immune infiltrate induced by chemotherapy have a prognostic impact. Complete pathological responses observed after six cycles of anthracycline-based chemotherapy are associated with an improvement of the ratio between CD8+ cytotoxic T lymphocytes (CTL) and immunosuppressive FOXP3+ regulatory T cells [2]. Thus, it appears that chemotherapy can indeed elicit anticancer immune responses. One important mechanism through which chemotherapy stimulates anticancer immunosurveillance consists in the induction of immunogenic cell death (ICD)[3]. ICD is a cell death modality that is preceded by cellular stress responses (in particular autophagy, endoplasmic reticulum stress, as well a type 1 interferon production) that affect the perception of dying cells and their corpses by the immune system. Premortem autophagy is required for the optimal release of ATP, and extracellular ATP is (one of) the major chemotactic factor(s) that attracts myeloid cells into the proximity of dying cancer cells. Endoplasmic reticulum (ER) stress facilitates the exposure of ER luminal proteins such as calreticulin on the surface of the plasma membrane, and surface-exposed calreticulin serves as a potent ‘eat-me’ signal facilitating the transfer of dead-cell antigens into immature dendritic cells. HMGB1, which leaks out from the nuclei of dead cells, stimulates the maturation of immature dendritic cells, which then can present tumorassociated antigens to CTL. Type 1 interferon is required for conditioning the tumor microenvironment to optimize the recruitment and action of CTL [3-5]. It is important to note that anthracyclines and oxaliplatin are efficient ICD inducers, perhaps explaining that these drugs can be successfully used for the adjuvant or neoadjuvant treatment of mammary and colorectal carcinomas, respectively. In contrast, cisplatin, which is widely used as the first-line treatment of lung cancer, is a relatively poor ICD inducer, presumably because it fails to stimulate an efficient ER stress response [3]. Many non-small cell lung cancers (NSCLC) are primarily resistant against cisplatin, a feature that can be explained by their metabolic characteristics. Thus, the levels of expression of pyridoxine kinase (PDXK) by NSCLC cells have a major prognostic impact on the survival of patients treated with cisplatin[6]. PDXK is the enzyme that converts cell-permeable pyridoxine (also called vitamin B6) into pyridoxine phosphate, the active metabolite that is trapped in cells and can serve Editorial