Vitamin C, From Supplement to Treatment: A Re-Emerging Adjunct for Cancer Immunotherapy?

Vitamin C (VitC), in addition to its role as a general antioxidant, has long been considered to possess direct anti-cancer activity at high doses. VitC acts through oxidant and epigenetic mechanisms, which at high doses can exert direct killing of tumor cells in vitro and delay tumor growth in vivo. Recently, it has also been shown that pharmacologic-dose VitC can contribute to control of tumors by modulating the immune system, and studies have been done interrogating the role of physiologic-dose VitC on novel adoptive cellular therapies (ACTs). In this review, we discuss the effects of VitC on anti-tumor immune cells, as well as the mechanisms underlying those effects. We address important unanswered questions concerning both VitC and ACTs, and outline challenges and opportunities facing the use of VitC in the clinical setting as an adjunct to immune-based anti-cancer therapies.

Discovery of Novel Inhibitors From Medicinal Plants for V-Domain Ig Suppressor of T-Cell Activation

V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint and is a type I transmembrane protein. VISTA is linked to immunotherapy resistance, and it is a potential immune therapeutic target, especially for triple-negative breast cancer. It expresses at a high concentration in regulatory T cells and myeloid-derived suppressor cells, and its functional blockade is found to delay tumor growth. A useful medicinal plant database for drug designing (MPD3), which is a collection of phytochemicals from diverse plant families, was employed in virtual screening against VISTA to prioritize natural inhibitors against VISTA. Three compounds, Paratocarpin K (PubChem ID: 14187087), 3-(1H-Indol-3-yl)-2-(trimethylazaniumyl)propanoate (PubChem ID: 3861164), and 2-[(5-Benzyl-4-ethyl-1,2,4-triazol-3-yl)sulfanylmethyl]-5-methyl-1,3,4-oxadiazole (PubChem ID: 6494266), having binding energies stronger than −6 kcal/mol were found to have two common hydrogen bond interactions with VISTA active site residues: Arg54 and Arg127. The dynamics of the compound–VISTA complexes were further explored to infer binding stability of the systems. Results revealed that the compound 14187087 and 6494266 systems are highly stable with an average RMSD of 1.31 Å. Further affirmation on the results was achieved by running MM-GBSA on the MD simulation trajectories, which re-ranked 14187087 as the top-binder with a net binding energy value of −33.33 kcal/mol. In conclusion, the present study successfully predicted natural compounds that have the potential to block the function of VISTA and therefore can be utilized further in experimental studies to validate their real anti-VISTA activity.

Folate-Targeted Monodisperse PEG-Based Conjugates Made by Chemo-Enzymatic Methods for Cancer Diagnosis and Treatment

This paper focuses on preliminary in vitro and in vivo testing of new bivalent folate-targeted PEGylated doxorubicin (DOX) made by modular chemo-enzymatic processes (FA2-dPEG-DOX2). A unique feature is the use of monodisperse PEG (dPEG). The modular approach with enzyme catalysis ensures exclusive γ-conjugation of folic acid, full conversion and selectivity, and no metal catalyst residues. Flow cytometry analysis showed that at 10 µM concentration, both free DOX and FA2-dPEG-DOX2 would be taken up by 99.9% of triple-negative breast cancer cells in 2 h. Intratumoral injection to mice seemed to delay tumor growth more than intravenous delivery. The mouse health status, food, water consumption, and behavior remained unchanged during the observation.

Exploring Chitosan-Shelled Nanobubbles to Improve HER2+ Immunotherapy Through Dendritic Cells Targeting

Immunotherapy is a valuable approach for the treatment of cancer. Nanotechnology-based delivery systems emerged as a powerful tool for improving immunotherapeutics. Therefore, their association have been proposed to overcome some biopharmaceutical limitations of immunotherapy. This work aims at designing a novel immunotherapeutic nanoplatform for the treatment of HER2+ breast cancer. Here, purposely-tailored chitosan-shelled nanobubbles (NBs) were developed for the loading of DNA vaccine. The NBs were then functionalized with anti-CD1a antibody to target dendritic cells (DCs). The NB formulations showed sizes of about 300 nm and a good physical stability up to 6 months stored at 4 °C. The in vitro characterization confirmed that these NBs were able to load DNA with a good encapsulation efficiency (82%). The antiCD1a-functionalized NBs targeted to DCs demonstrated the capability to induce activation of DCs both in human and mouse models, and elicit a specific immune response able to delay tumor growth in vivo in mice. The results are the proof of concept that DC-targeted chitosan nanobubbles loaded with tumor vaccine may provide an attractive nanotechnology approach for the future immunotherapeutic treatment of cancer.

Evaluation of chemotherapy and P2Et extract combination in ex-vivo derived tumor mammospheres from breast cancer patients

The main cause of death by cancer is metastasis rather than local complications of primary tumors. Recent studies suggest that breast cancer stem cells (BCSCs), retains the ability to self-renew and differentiate to repopulate the entire tumor, also, they have been associated with resistance to chemotherapy and tumor recurrence, even after tumor resection. Chemotherapy has been implicated in the induction of resistant phenotypes with highly metastatic potential. Naturally occurring compounds, especially phytochemicals such as P2Et, can target different populations of cancer cells as well as BCSC, favoring the activation of immune response via immunogenic tumor death. Here, we evaluated the presence of BCSC as well as markers related to drug resistance in tumors obtained from 78 patients who had received (or not) chemotherapy before surgery. We evaluated the ex vivo response of patient tumor-derived organoids (or mammospheres) to chemotherapy alone or in combination with P2Et. A xenotransplant model engrafted with MDA-MB-468 was used to evaluate in vivo the activity of P2Et, in this model P2Et delay tumor growth. We show that patients with luminal and TNBC, and those who received neoadjuvant therapy before surgery have a higher frequency of BCSC. Further, the treatment with P2Et in mammospheres and human breast cancer cell lines improve the in vitro tumor death and decrease its viability and proliferation together with the release of immunogenic signals. P2Et could be a good co-adjuvant in antitumor therapy in patients, retarding the tumor growth by enabling the activation of the immune response.

Delay Tumor Growth Properties of LA-PEG-G Molecule and Its' Application as Drug Carrier

LA–PEG–G molecule was prepared through the covalent conjugation of linoleic acid, polyethylene glycol and guanosine. LA–PEG–G molecule can self-assemble into spherical aggregate in aqueous solution. The size of the LA–PEG–G aggregate was approximately 132.1 ± 13.718 nm, and the Zeta potential was −36.3 ± 0.9644 mv. The loading rate of LA–PEG–G aggregates to Dox was 84.62 ± 1.810%. In vitro release experiments showed that Dox release from the LA–PEG–G–Dox nanomedicine was slow-release. Cell experiments showed that LA–PEG–G aggregates have low cytotoxicity, and the relative cancer cells survival rate decreased with the increasing of time and LA–PEG–G–Dox nanomedicine concentration. In vivo experiments showed that LA–PEG–G–Dox nanomedicine can inhibit tumor growth, and the LA–PEG–G aggregate could also delay the tumor growth which is very important to play the synergistic antitumor effect with the anticancer drug. Serum biochemistry showed that LA–PEG–G–Dox nanomedicine which reduced the Dox toxicity had very good antitumor effect. The tumor tissue sections indicated that LA–PEG–G–Dox nanomedicine can effectively induce tumor cell apoptosis, and finally cause tissue necrosis to achieve tumor treatment.

Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.