Alternative immune checkpoints in immunoregulatory profile of cancer stem cells

Tumor-mediated bypass of immune checkpoint inhibitor (ICI) therapy with anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1, also called B7–H1 or CD274) or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is a challenge of current years in the area of cancer immunotherapy. Alternative immune checkpoints (AICs) are molecules beyond the common PD-1, PD-L1 or CTLA-4, and are upregulated in patients who show low/no ICI responses. These are members of B7 family including B7–H2 (ICOS-L), B7–H3 (CD276), B7–H4 (B7x), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7–H6, HHLA2 (B7–H5/B7–H7) and catabolic enzymes like indoleamine 2,3-dioxygenase 1 (IDO1), and others that are also contributed to the regulation of tumor immune microenvironment (TIME). There is also strong evidence supporting the implication of AICs in regulation of cancer stemness and expanding the population of cancer stem cells (CSCs). CSCs display immunoregulatory capacity and represent multiple immune checkpoints either on their surface or inside. Besides, they are active promoters of resistance to the common ICIs. The aim of this review is to investigate interrelations between AICs with stemness and differentiation profile of cancer. The key message of this paper is that targeted checkpoints can be selected based on their impact on CSCs along with their effect on immune cells. Studies published so far mainly focused on immune cells as a target for anti-checkpoints. Ex vivo engineering of extracellular vesicles (EVs) equipped with CSC-targeted anti-checkpoint antibodies is without a doubt a key therapeutic target that can be under consideration in future research

The impact of oncolytic adenoviral therapy on the therapeutic efficacy of PD-1/PD-L1 blockade

Immunotherapy has revolutionized treatment of cancer during the last decades. Oncolytic virotherapy has also emerged as a strategy to fight against cancer cells both via lysis of malignant cells and activating immune responses. Accepted as a logical strategy, combination of monoclonal antibodies particularly against the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) is introduced to improve clinical responses to immune checkpoint inhibitors (ICIs). Accordingly, Talimogene laherparepvec (T-VEC) has received approval for clinical use, while a number of oncolytic Adenoviruses (Ads) are being investigated in clinical trials of malignancies. Combination of oncolytic Ads with PD-1/PD-L1 inhibitors have shown potentials in promoting responses to ICIs, changing the tumor microenvironment, inducing long-term protection against tumor, and promoting survival among mice models of malignancies. Regarding the increasing importance of oncolytic Ads in combination therapy of cancers, in this review we decide to outline recent studies in this field

Strategies for Application of Extracellular Vesicles in Solid Cancer Therapy

Background and Aim: Extracellular vesicles (EVs) are key players in cellular communication and signaling in the health status and diseases. EVs have rather small size and long half-life upon secretion into circulation. This long half-life along with their immune privileged profile and the ability to carry biotherapeutics to the target cells have made EVs an issue of prominent current interest among scientists as an alternative schedule in cancer therapy. Materials and Methods: PubMed and Google scholar were searched for relevant articles from journals with high impact factor. Among 400 articles found, 40 articles met the criteria for interpretation and were selected for descriptive review. Original and review articles published in the last ten years were used in this study. Results: Tumor-derived EVs can be targeted for reducing cancer cell survival and increasing their apoptosis. They are also applicable for drug delivery to primary or metastatic tumors. An effective approach is to load nanoparticles into EVs for targeting a specific cell type in tumor ecosystem. Their application in nano delivery systems for cancer therapy has been the focus of attention. Conclusion: The current studies have focused on the possibility of using EVs as biomarkers in several diseases, as targets to be removed for recovery of the patient health, and as vehicles for immunotherapy. In this review article, we discussed the importance of EV suppression or EV-based strategy for targeting solid cancer

Bypassing anti-PD-(L)1 therapy: Mechanisms and management strategies

Resistance to immune checkpoint inhibitors (ICIs) is a major issue of the current era in cancer immunotherapy. Immune evasion is a multi-factorial event, which occurs generally at a base of cold immunity. Despite advances in the field, there are still unsolved challenges about how to combat checkpoint hijacked by tumor cells and what are complementary treatment strategies to render durable anti-tumor outcomes. A point is that anti-programed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) is not the solo path of immune escape, and responses in many types of solid tumors to the PD-1/PD-L1 inhibitors are not satisfactory. Thus, seeking mechanisms inter-connecting tumor with its immune ecosystem nearby unravel more about resistance mechanisms so as to develop methods for sustained reinvigoration of immune activity against cancer. In this review, we aimed to discuss about common and specific paths taken by tumor cells to evade immune surveillance, describing novel detection strategies, as well as suggesting some approaches to recover tumor sensitivity to the anti-PD-(L)1 therapy based on the current knowledge

Genomic Instability and Carcinogenesis of Heavy Charged Particles Radiation: Clinical and Environmental Implications

One of the uses of ionizing radiation is in cancer treatment. The use of heavy charged particles for treatment has been introduced in recent decades because of their priority for deposition of radiation energy in the tumor, via the Bragg peak phenomenon. In addition to medical implications, exposure to heavy charged particles is a crucial issue for environmental and space radiobiology. Ionizing radiation is one of the most powerful clastogenic and carcinogenic agents. Studies have shown that although both low and high linear energy transfer (LET) radiations are carcinogenic, their risks are different. Molecular studies have also shown that although heavy charged particles mainly induce DNA damage directly, they may be more potent inducer of endogenous generation of free radicals compared to the low LET gamma or X-rays. It seems that the severity of genotoxicity for non-irradiated bystander cells is potentiated as the quality of radiation increases. However, this is not true in all situations. Evidence suggests the involvement of some mechanisms such as upregulation of pro-oxidant enzymes and change in the methylation of DNA in the development of genomic instability and carcinogenesis. This review aimed to report important issues for genotoxicity of carcinogenic effects of heavy charged particles. Furthermore, we tried to explain some mechanisms that may be involved in cancer development following exposure to heavy charged particles

Intentos de reforma en la universidad de Valladolid durante el reinado de Carlos IV

Actas de la I Reunión Científica de la Asociación Española de Historia Moderna, Madrid, 11 al 13 de diciembre de 1989Peer reviewe