Cancer Nano-Immunotherapy from the Injection to the Target: The Role of Protein Corona.

Immunotherapy has become a promising cancer therapy, improving the prognosis of patients with many different types of cancer and offering the possibility for long-term cancer remission. Nevertheless, some patients do not respond to these treatments and immunotherapy has shown some limitations, such as immune system resistance or limited bioavailability of the drug. Therefore, new strategies that include the use of nanoparticles (NPs) are emerging to enhance the efficacy of immunotherapies. NPs present very different pharmacokinetic and pharmacodynamic properties compared with free drugs and enable the use of lower doses of immune-stimulating molecules, minimizing their side effects. However, NPs face issues concerning stability in physiological conditions, protein corona (PC) formation, and accumulation in the target tissue. PC formation changes the physicochemical and biological properties of the NPs and in consequence their therapeutic effect. This review summarizes the recent advances in the study of the effects of PC formation in NP-based immunotherapy. PC formation has complex effects on immunotherapy since it can diminish ("immune blinding") or enhance the immune response in an uncontrolled manner ("immune reactivity"). Here, future perspectives of the field including the latest advances towards the use of personalized protein corona in cancer immunotherapy are also discussed.

Nanoparticles and trained immunity: Glimpse into the future.

Emerging evidences show that innate immune cells can display changes in their functional programs after infection or vaccination, which lead to immunomodulation (increased or reduced responsiveness) upon secondary activation to the same stimuli or even to a different one. Innate cells acquire features of immunological memory, nowadays using the new term of "trained immunity" or "innate immune memory", which is different from the specific memory immune response elicited by B and T lymphocytes. The review focused on the concept of trained immunity, mostly on myeloid cells. Special attention is dedicated to the pathogen recognition along the evolution (bacteria, plants, invertebrate and vertebrate animals), and to techniques used to study epigenetic reprogramming and metabolic rewiring. Nanomaterials can be recognized by immune cells offering a very promising way to learn about trained immunity. Nanomaterials could be modified in order to immunomodulate the responses ad hoc. Many therapeutic possibilities are opened, and they should be explored.

Natural killer (NK) cell-based immunotherapies and the many faces of NK cell memory: A look into how nanoparticles enhance NK cell activity.

Natural killer (NK) cells are lymphocytes able to exert potent antitumor and antiviral functions by different means. Besides their classification as innate lymphoid cells (ILCs), NK cells exhibit memory-like and memory responses after cytokine preactivation, viral infections and hapten exposure. Multiple NK cell-based immunotherapies have been developed and are currently being tested, including the possibility to translate the NK cell memory responses into the clinic. Nevertheless, still there is a need to improve these therapies, especially for the treatment of solid tumors, and nanotechnology represents an attractive option to increase NK cell effector functions against transformed cells. In this article, we review the basis of NK cell activity, the diversity of the NK cell memory responses and the current NK cell-based immunotherapies that are being used in the clinic. Furthermore, we take a look into nanotechnology-based strategies targeting NK cells to modulate their responses for effective immunotherapy.

NK Cell-Based Immunotherapy in Renal Cell Carcinoma.

Natural killer (NK) cells are cytotoxic lymphocytes that are able to kill tumor cells without prior sensitization. It has been shown that NK cells play a pivotal role in a variety of cancers, highlighting their relevance in tumor immunosurveillance. NK cell infiltration has been reported in renal cell carcinoma (RCC), the most frequent kidney cancer in adults, and their presence has been associated with patients' survival. However, the role of NK cells in this disease is not yet fully understood. In this review, we summarize the biology of NK cells and the mechanisms through which they are able to recognize and kill tumor cells. Furthermore, we discuss the role that NK cells play in renal cell carcinoma, and review current strategies that are being used to boost and exploit their cytotoxic capabilities.

Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma.

Histone deacetylase 6 (HDAC6) is an epigenetic modifier that is an attractive pharmacological target in cancer. In this work, we show that HDAC6 is elevated in glioblastoma, the most malignant and common brain tumor in adults, in which its high levels correlate with poor patient survival and is more abundant in glioma stem cell subpopulation. Moreover, we identified a new small-molecule inhibitor of HDAC6, which presents strong sensitivity for HDAC6 inhibition and exerts high cytotoxic activity, alone or in combination with temozolomide. It is also able to significantly reduce tumor growth in vivo. Transcriptomic analysis of patient-derived glioma stem cells revealed an increase in cell differentiation and cell death pathways, as well as a decrease in cell-cycle activity and cell division by the treatment with the compound. Finally, the comparison with a pan-HDAC inhibitor, Vorinostat (SAHA), or HDAC6-specific inhibitor, Tubastatin A, showed higher target specificity and antitumor activity of the new HDAC6 inhibitor. In conclusion, our data reveal the efficacy of a novel HDAC6 inhibitor in glioblastoma preclinical setting.