Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages

Abstract

BackgroundLysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment.MethodsThe effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry.ResultsHCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8+ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8+ T cell infiltration into the tumour microenvironment.ConclusionsHCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8+ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0938-5) contains supplementary material, which is available to authorized users.

Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters

“…Together with the assumption that it is a P-gp substrate, this inhibition is most likely competitive. Recently, another mechanism for P-gp inhibition has been demonstrated: in cancer cells, hydroxychloroquine inactivates P-gp located in lysosomes by increasing lysosomal pH (after 12 h of incubation), thus sensitising cells to chemotherapeutic P-gp substrates such as doxorubicin [ 43 ]. However, the calcein assay applied in our study measures short-term effects (total incubation time only 45 min in the P388 cell system); thus, it can be excluded that the effect observed can be attributed to a (sub-acute) increase in lysosomal pH.…”

Immune Modulation as a Therapeutic Option During the SARS-CoV-2 Outbreak: The Case for Antimalarial Aminoquinolines

“…Inhibition of lysosomal trafficking affects upstream (endocytosis) but also downstream (autophagy) processes. Autophagy inhibition is currently fueling sustained interest in CQ/HCQ as chemosensitizers for cancer therapy ( 7 , 9 , 22 , 44 – 46 ). However, autophagy inhibition also modulates dendritic cell (DC) and macrophage activation and polarization ( 47 , 48 ).…”

“…The monocyte-macrophage system is an important target of CQ/HCQ, especially as it orchestrates downstream modulation of T cell populations ( 7 , 43 ).…”

“…CQ/HCQ are able to re-tune tumor-associated macrophages from a permissive M2 to an antitumor M1 phenotype, resulting in decreased immunosuppressive cell infiltration, and enhanced antitumor T-cell immunity ( 7 , 43 ). CQ treatment induced Ca 2+ release from lysosomes, which in turn activated NF-κB, but also TFEB ( 7 , 43 ). To our knowledge, the apparent contradiction between the classical view of CQ-induced inhibition of the M1 phenotype and experiments showing macrophage reprogramming from M2 to M1 has not been addressed yet.…”

“…Azithromycin administration at the early stage of a bacterial infection would promote host defenses, while at later stages with ongoing inflammation this molecule displays an array of immunomodulatory effects spanning epithelial cell protection, airway smooth muscle relaxation, inhibition of fibroblast proliferation, downregulation of neutrophil oxidative and chemotactic responses, extensive macrophage (including alveolar macrophage) modulation with M1 to M2 repolarization and inhibition of TNFα, GM-CSF (Granulocyte-macrophage colony-stimulating factor) and several proinflammatory cytokine production, and finally dendritic cell maturation toward a regulatory phenotype ( 119 ). Moreover, azithromycin accumulates in lysosomes, and HCQ has been proposed as a chemosensitizer for improved biodisponibility and prolonged efficacy of lysosomotropic drugs ( 7 ). The synergy between HCQ and azithromycin supports the emerging concept of treating SARS-CoV-2 infections with immunomodulators/immunosuppressants ( 119 , 120 ), at least until a specific antiviral treatment is available.…”