Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapiesF.T.A. was supported by the AECC (“Asociación Española Contra el Cáncer, Spain). E.D. was supported by AIRC (Associazione Italiana per la Ricerca contro il Cancro)S

Cellular and Molecular Mechanisms Underlying Glioblastoma and Zebrafish Models for the Discovery of New Treatments

Glioblastoma (GBM) is the most common of all brain malignant tumors; it displays a median survival of 14.6 months with current complete standard treatment. High heterogeneity, aggressive and invasive behavior, the impossibility of completing tumor resection, limitations for drug administration and therapeutic resistance to current treatments are the main problems presented by this pathology. In recent years, our knowledge of GBM physiopathology has advanced significantly, generating relevant information on the cellular heterogeneity of GBM tumors, including cancer and immune cells such as macrophages/microglia, genetic, epigenetic and metabolic alterations, comprising changes in miRNA expression. In this scenario, the zebrafish has arisen as a promising animal model to progress further due to its unique characteristics, such as transparency, ease of genetic manipulation, ethical and economic advantages and also conservation of the major brain regions and blood–brain–barrier (BBB) which are similar to a human structure. A few papers described in this review, using genetic and xenotransplantation zebrafish models have been used to study GBM as well as to test the anti-tumoral efficacy of new drugs, their ability to interact with target cells, modulate the tumor microenvironment, cross the BBB and/or their toxicity. Prospective studies following these lines of research may lead to a better diagnosis, prognosis and treatment of patients with GBMF.T.A. has been supported by the AECC (“Asociación Española Contra el Cáncer”, Spain). We would also like to thank the following: the Talento Program from Madrid Government, Spain (2017-T1/BMD-5333); Convocatoria 2018 de proyectos de I+D+i «RETOS INVESTIGACIÓN» (RTI2018-095061-B-I00) (to C.M.R.); “Convocatoria de ayudas para la contratación de ayudantes de investigación” (PEJ-2018-AI/BMD-9724) (to M.T.-P.); the Xunta de Galicia Pre-doctoral Fellowship (ED481A-2018/095) (to A.P.L.)S

Mannose-modified hyaluronic acid nanocapsules for the targeting of tumor-associated macrophages

Tumor-associated macrophages (TAMs), a class of immune cells that play a key role in tumor immunosuppression, are recognized as important targets to improve cancer prognosis and treatment. Consequently, the engineering of drug delivery nanocarriers that can reach TAMs has acquired special relevance. This work describes the development and biological evaluation of a panel of hyaluronic acid (HA) nanocapsules (NCs), with different compositions and prepared by different techniques, designed to target macrophages. The results showed that plain HA NCs did not significantly influence the polarization of M0 and M2-like macrophages towards an M1-like pro-inflammatory phenotype; however, the chemical functionalization of HA with mannose (HA-Man) led to a significant increase of NCs uptake by M2 macrophages in vitro and to an improved biodistribution in a MN/MNCA1 fibrosarcoma mouse model with high infiltration of TAMs. These functionalized HA-Man NCs showed a higher accumulation in the tumor compared to non-modified HA NCs. Finally, the pre-administration of the liposomal liver occupying agent Nanoprimer™ further increased the accumulation of the HA-Man NCs in the tumor. This work highlights the promise shown by the HA-Man NCs to target TAMs and thus provides new options for the development of nanomedicine and immunotherapy-based cancer treatmentsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the 2^2-INTRATARGET project (A20/00028) funded by the ISCIII under the umbrella of the ERA NET EuroNanoMed GA N 723770 of the EU Horizon 2020 Research and Innovation Programme. This work was also supported by the Xunta de Galicia (ED431C 2018/30, and “Centro singular de investigación de Galicia” accreditation 2019 − 2022, ED431G2019/03), and the European Union (European Regional Development Fund-ERDF)S

Targeting hypoxic tumors with oxygen and gadolinium enriched nanozeolites

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Iron loaded EMT nanosized zeolite with high affinity towards CO 2 and NO

CERVOXY COLLInternational audienceThe preparation of iron-loaded nanosized zeolite with EMT-type structure (Fe-EMT) is reported. The sorption capacity of the Fe-EMT zeolite crystals for NO and CO2 is evaluated. The application of Fe-EMT zeolite as a gas delivery system with high capacity for CO2 and NO in biomedicine is considered. Therefore the toxicity of the pure EMT and Fe-EMT zeolite nanocrystals is studied. Primary culture of astrocytes was exposed to zeolite nanocrystals. In addition, two human cell lines, U87-MG glioblastoma and HEK-293T were used. Cells were exposed to zeolites nanocrystals with concentrations of 50, 100 and 400 μg/ml for 24 h and 48 h. Cytotoxicity was assessed by a cell viability assay and no alteration of cell viability exposed to zeolite nanoparticles was observed

Incorporation of trivalent cations in NaX zeolite nanocrystals for the adsorption of O 2 in the presence of CO 2

CERVOXY COLLInternational audienceThe O2 and CO2 sorption properties of nanosized zeolite X with faujasite type structure through a partial ionic exchange of sodium (Na +) by trivalent cations (Gd 3+ and Ce 3+) were evaluated. Three faujasite samples were studied, the as-synthesized Na-X possessing Na + solely, and the modified samples Na-Gd-X and Na-Ce-X containing Gd 3+ (1.8 wt%) and Ce 3+ (0.82 wt%), respectively. Incorporating scarce amounts of trivalent cations modified the adsorption affinity of zeolites towards O2 and CO2 as demonstrated by in situ Fourier-transform infrared spectroscopy (FTIR). While Na-Ce-X encounters the highest O2 physisorption capacity, the Na-Gd-X is adsorbing the highest quantities of molecular CO2. All three samples exhibit the chemisorbed CO2 in the form of carbonates, while the Na-X stores carbonates in monodentate and polydentate forms, the Na-Gd-X and Na-Ce-X allow the formation of polydentate carbonates only. Density functional theory (DFT) calculations revealed that trivalent cations tend to adsorb gases through two cations simultaneously which explains the presence of polydentate carbonates exclusively in the corresponding modified zeolites. The DFT results confirmed the higher affinity of Na-Gd-X and Na-Ce-X nanocrystals towards O2 in the presence of CO2. The affinity of Na-Gd-X and Na-Ce-X nanocrystals towards O2 opens the door of their use as oxygen transporters for medical applications where CO2 is constantly present. The toxicity of the nanosized zeolites and their performance in O2 release are reported too

Copper exchanged FAU nanozeolite as non-toxic nitric oxide and carbon dioxide gas carrier

CERVOXY COLLInternational audienc

Copper exchanged FAU nanozeolite as non-toxic nitric oxide and carbon dioxide gas carrier

CERVOXY COLLInternational audienc

Innate and Adaptive Responses of Intratumoral Immunotherapy with Endosomal Toll-Like Receptor Agonists

Toll-like receptors (TLRs) are natural initial triggers of innate and adaptive immune responses. With the advent of cancer immunotherapy, nucleic acids engineered as ligands of endosomal TLRs have been investigated for the treatment of solid tumors. Despite promising results, their systemic administration, similarly to other immunotherapies, raises safety issues. To overcome these problems, recent studies have applied the direct injection of endosomal TLR agonists in the tumor and/or draining lymph nodes, achieving high local drug exposure and strong antitumor response. Importantly, intratumoral delivery of TLR agonists showed powerful effects not only against the injected tumors but also often against uninjected lesions (abscopal effects), resulting in some cases in cure and antitumoral immunological memory. Herein, we describe the structure and function of TLRs and their role in the tumor microenvironment. Then, we provide our vision on the potential of intratumor versus systemic delivery or vaccination approaches using TLR agonists, also considering the use of nanoparticles to improve their targeting properties. Finally, we collect the preclinical and clinical studies applying intratumoral injection of TLR agonists as monotherapies or in combination with: (a) other TLR or STING agonists; (b) other immunotherapies; (c) radiotherapy or chemotherapy; (d) targeted therapies