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  • br Autophagy inducers Macroautophagy is often seen

    2024-04-02


    Autophagy inducers Macroautophagy is often seen as a cellular process capable of increasing the fitness of Kifunensine and overcome resistance to several forms of stress [9], [10]. As discussed above, it has been proposed by several authors that an effective strategy for enhancing sensitivity of cancer cells to radiotherapy and/or chemotherapy can be the recurrence to autophagic inhibitors, especially in those cancers driven by K-ras mutations [38], [39] and B-raf[40], [41], as reported above (reviewed in Refs. [33], [57], [58]) (Fig. 1). However, as pointed out by Kroemer’s group, “sustained long-term effects of successful treatments can only be explained by anticancer immune responses” [56]. The arguments sustained by these authors deal with the need to reconstitute the efficacy of immunosurveillance in malignant cells and organisms affected by cancer. The transition from a healthy cell to its pre-malignant form is normally blocked by a functional immune response since cancer cells are antigenically distinct from their “normal” counterpart and, for this reason, eliminated from the tissue/organism. When immunosurveillance fails, cancer cells escape and initiate the multistep process leading to metastatic tumours. Consequently, chemo- and radiotherapies can be effective if they restore immunosurveillance. Accumulating evidence is going in this direction. As an example, in multiple myeloma, several therapeutic strategies are currently explored to reverse natural killer dysfunctions, which impede killing of transformed plasma cells, such as Pembrolizumab (anti PD-1 receptor) in combination with Lenalidomide, or Daratumumab (CD38 ligand) associated with Bortezomib and Dexamethasone [59]. In general, several forms of radiation and photodynamic therapies, as well as chemotherapeutic drugs, such as oxaliplatin, cyclophosphamide, doxorubicin, trigger immunogenic cell death (ICD) in cancer cells, a specific form of cell death which culminates in the activation of dendritic cells and consequent activation of specific T cell response [60], [61]. In this scenario, the important novelty is represented by the positive role of autophagy. In fact, the activation of this process, not its inhibition, may contribute to restore immunosurveillance in cancer cells. In an excellent review recently published by Pietrocola et al. [62], the authors deeply analyzed the immunological consequences of the involvement of autophagy in cancer therapy. They agree that the inhibition of autophagy may increase cancer cell death following chemotherapy or radiation therapy. A good example is the demonstration in canine patients, applying comparative in vivo oncology-arrayed microinjection technology, doxorubicin-induced ICD recruiting immune cell populations (largely macrophages) directly into regions of cell death and accumulating CD3-positive T cells surrounding the perimeter of the tumour cell death zone [63]. PS-1001, a dimeric chloroquine autophagy inhibitor [64], was able to bypass the subset of doxorubicin-resistant tumours (about 50% of the total cases), by increasing macrophage recruitment and switching macrophage polarization toward the antitumor M1 macrophage state [63]. However, the point raised by Pietrocola et al. is that inhibiting autophagy may also favor relapse preventing the activation of immune responses against tumour. On the opposite, autophagy inducers may improve the efficacy of the immune system in eradicating cancer cells from the organism [62]. To this regard, a key example is represented by the role of nutrient starvation. In the absence of activating mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway, which suppresses autophagy via IGF1R (insulin-like growth factor 1 receptor), tumour progression is prevented in both cellular and mice model where nutrient deprivation is experimentally applied [65]. Similarly, the synergism between chemotherapy and fasting can be reverted or eliminated in not autophagy-competent tumours, like those in which ATG5 had been depleted by transfection with a construct encoding a specific short hairpin RNA (shRNA) [66]. On the opposite, in xenograft mice, starved for 48 h before chemotherapeutic treatment significantly reduced side effects and high-dose toxicity compared to mice fed with standard diets [67]. The safety of 24–72 h short-term starvation before chemotherapy administration has been also reproduced in cancer patients, where 8–30% reduction in IGF-1 levels was measured in the fasting cohorts [68]. Since water and short-term starvation is a demanding treatment in both mice and patients, the effects of a fasting-mimicking diet, low in proteins, carbohydrates and calories has been tested alone or in combination with chemotherapy, resulting in T-cell-dependent elimination of cancer cells throughout the stimulation of the hematopoietic system and the increased CD8 + -dependent tumour-cytotoxicity [69].