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Renal cell carcinoma (RCC) is the deadliest form of urological cancer and is projected to be the fourth most common neoplasm in the USA in males by 2040. In addition to the current poor prognosis with 5-year survival rates hardly reaching 15%, the prevalence of resistance to currently available systemic therapies has also established an urgent need to develop new treatment regimen(s) for advanced RCC. Interferon-stimulated gene 15 (ISG15) is the first identified ubiquitin-like modifier and has been intensively studied for its central role in innate immunity against intracellular pathogens. However, in this study, we identified ISG15 as a novel tumor-associated antigen and prognostic marker in RCC. Further, we therapeutically targeted elevated ISG15 expression by means of a Listeria monocytogenes (Lm)-based vaccine, designated Lm-LLO-ISG15, in both subcutaneous and orthotopic RCC mouse models. Treatment with Lm-LLO-ISG15 resulted in an influx of tumor-infiltrating effector T cells and significant anti-tumor efficacy in both subcutaneous and orthotopic RCC tumor models. Treatment with Lm-LLO-ISG15 also generated a robust interferon-gamma response and attracted a larger pool of polyfunctional T cells into the tumor microenvironment. Importantly, the therapeutic efficacy of Lm-LLO-ISG15 in RCC is comparable to that of anti-PD-1 and sunitinib, the current frontline therapies for RCC patients. Collectively, our work illustrates that targeting ISG15 in RCC with a CTL-based immunotherapy such as Lm-LLO-ISG15 is a promising and potentially translatable therapeutic strategy to enhance survival in RCC patients. [ABSTRACT FROM AUTHOR]

CD105 (endoglin) is a transmembrane protein that functions as a TGF-beta coreceptor and is highly expressed on endothelial cells. Unsurprisingly, preclinical and clinical evidence strongly suggests that CD105 is an important contributor to tumor angiogenesis and tumor progression. Emerging evidence suggests that CD105 is also expressed by tumor cells themselves in certain cancers such as renal cell carcinoma (RCC). In human RCC tumor cells, CD105 expression is associated with stem cell-like properties and contributes to the malignant phenotype in vitro and in xenograft models. However, as a regulator of TGF-beta signaling, there is a striking lack of evidence for the role of tumor-expressed CD105 in the anti-tumor immune response and the tumor microenvironment. In this study, we report that tumor cell-expressed CD105 potentiates both the in vitro and in vivo tumorigenic potential of RCC in a syngeneic murine RCC tumor model. Importantly, we find that tumor cell-expressed CD105 sculpts the tumor microenvironment by enhancing the recruitment of immunosuppressive cell types and inhibiting the polyfunctionality of tumor-infiltrating CD4+ and CD8+ T cells. Finally, while CD105 expression by endothelial cells is a well-established contributor to tumor angiogenesis, we also find that tumor cell-expressed CD105 significantly contributes to tumor angiogenesis in RCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite their potential and promising anti-tumor efficacy, previously developed cancer vaccines targeting different tumor-associated antigens for colorectal cancer (CRC) have not yet proven to be successful. Interferon-stimulated gene 15 (ISG15) is emerging as an important oncoprotein with a potential diagnostic signature and therapeutic target for a multitude of cancer, including CRC. In this study, we investigated the therapeutic efficacy of Listeria-based vaccines targeting ISG15 (Lm-LLO-ISG15) in CRC. We found that the Lm-LLO-ISG15 vaccination results in anti-tumor efficacy against the MC38 tumor model by recruiting cytotoxic T lymphocytes and leading to a more favorable effector to regulatory T cell ratio (Teff/Treg) in the tumor microenvironment. Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in both men and women in the United States. While immune checkpoint inhibitor (ICI) therapy is demonstrating remarkable clinical responses, the resistance and immune-related toxicities associated with ICIs demonstrate the need to develop additional immunotherapy options for CRC patients. Cancer vaccines represent a safe and promising treatment approach for CRC. As previously developed tumor-associated antigen (TAA)-based cancer vaccines for CRC are not demonstrating promising results, we propose that interferon-stimulated gene 15 (ISG15) is a novel TAA and therapeutic target for CRC. Our work demonstrates the anti-tumor efficacy of a Listeria-based vaccine targeting ISG15, designated Lm-LLO-ISG15, in an immunocompetent CRC murine model. The Lm-LLO-ISG15-mediated anti-tumor response is associated with an increased influx of functional T cells, higher production of multiple intracellular cytokines response, a lower number of regulatory T cells, and a greater ratio of effector to regulatory T cells (Teff/Treg) in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Anti-PD-1 and oncolytic viruses (OVs) have non-overlapping anti-tumor mechanisms, since each agent works at different steps of the cancer-immunity cycle. Evidence suggests that OVs improve therapeutic responses to anti-PD-1 therapy by reversing immunosuppressive factors, increasing the number and diversity of infiltrating lymphocytes, and promoting PD-L1 expression in both injected and non-injected tumors. Many studies in preclinical models suggest that the timing of anti-PD-1 administration influences the therapeutic success of the combination therapy (anti-PD-1 + OV). Therefore, determining the appropriate sequencing of agents is of critical importance to designing a rationale OV-based combinational clinical trial. Currently, the combination of anti-PD-1 and OVs are being delivered using various schedules, and we have classified the timing of administration of anti-PD-1 and OVs into five categories: (i) anti-PD-1 lead-in → OV; (ii) concurrent administration; (iii) OV lead-in → anti-PD-1; (iv) concurrent therapy lead-in → anti-PD-1; and (v) OV lead-in → concurrent therapy. Based on the reported preclinical and clinical literature, the most promising treatment strategy to date is hypothesized to be OV lead-in → concurrent therapy. In the OV lead-in → concurrent therapy approach, initial OV treatment results in T cell priming and infiltration into tumors and an immunologically hot tumor microenvironment (TME), which can be counterbalanced by engagement of PD-L1 to PD-1 receptor on immune cells, leading to T cell exhaustion. Therefore, after initial OV therapy, concurrent use of both OV and anti-PD-1 is critical through which OV maintains T cell priming and an immunologically hot TME, whereas PD-1 blockade helps to overcome PD-L1/PD-1-mediated T cell exhaustion. It is important to note that the hypothetical conclusion drawn in this review is based on thorough literature review on current understanding of OV + anti-PD-1 combination therapies and rhythm of treatment-induced cancer-immunity cycle. A variety of confounding factors such as tumor types, OV types, presence or absence of cytokine transgenes carried by an OV, timing of treatment initiation, varying dosages and treatment frequencies/duration of OV and anti-PD-1, etc. may affect the validity of our conclusion that will need to be further examined by future research (such as side-by-side comparative studies using all five treatment schedules in a given tumor model). [ABSTRACT FROM AUTHOR]

Molecular biomarkers that interact with the vascular and immune compartments play an important role in the progression of solid malignancies. CD105, which is a component of the transforming growth factor beta (TGF β) signaling cascade, has long been studied for its role in potentiating angiogenesis in numerous cancers. In renal cell carcinoma (RCC), the role of CD105 is more complicated due to its diverse expression profile on the tumor cells, tumor vasculature, and the components of the immune system. Since its discovery, its angiogenic role has overshadowed other potential functions, especially in cancers. In this review, we aim to summarize the recent evidence and findings of the multifunctional roles of CD105 in angiogenesis and immunomodulation in the context of the various subtypes of RCC, with a specific emphasis on the clear cell RCC subtype. Since CD105 is an established biomarker and tumor antigen, we also provide an update on the preclinical and clinical applications of CD105 as a therapeutic platform in RCC. • CD105 is a biomarker that is well characterized for its involvement in both normal and tumor angiogenesis. • CD105 potentiates renal cell carcinoma's resistant and malignant nature. • CD105 is expressed on tumor cells, endothelial cells, and immune cells in renal cell carcinoma. • The vast expression profile of CD105 in RCC is a potential avenue for active immunotherapeutic targeting. [ABSTRACT FROM AUTHOR]

Among the plethora of defense mechanisms which a host elicits after pathogen invasion, type 1 interferons play a central role in regulating the immune system's response. They induce several interferon-stimulated genes (ISGs) which play a diverse role once activated. Over the past few decades, there have been several studies exploring the role of ISGs in cancer and ISG15 is among the most studied for its pro and anti-tumorigenic role. In this review, we aim to provide an update on the recent observations and findings related to ISG15 in cancer. We provide a brief overview about the initial observations and important historical findings which helped scientists understand structure and function of ISG15. We aim to provide an overview of ISG15 in cancer with an emphasis on studies which delve into the molecular mechanism of ISG15 in modulating the tumor microenvironment. Further, the dysregulation of ISG15 in cancer and the molecular mechanisms associated with its pro and anti-tumor roles are discussed in respective cancer types. Finally, we discuss multiple therapeutic applications of ISG15 in current cancer therapy. • ISG15 is emerging as an important proto-oncoprotein, a potential prognostic biomarker and therapeutic target for cancer. • ISG15 plays a contradictory role in cancers and is currently studied for its pro and anti-tumorigenic role. • Therapeutic administered recombinant ISG15 could be beneficial. • Overexpression of ISG15 is an avenue that can be exploited for immunotherapeutic targeting by cancer vaccines. [ABSTRACT FROM AUTHOR]

To determine if dietary fish oil protects against colon cancer by decreasing oxidative DNA damage at the initiation stage of colon tumorigenesis, oxidative DNA damage, proliferation, and apoptosis were assessed by colonic crypt cell position using quantitative immunohistochemical analysis of 8-hydroxydeoxyguanosine (8-OHdG), Ki-67, and TUNEL assay, respectively. Sixty rats were provided one of two diets (corn oil or fish oil) and dextran sodium sulfate (DSS, an inducer of oxidative DNA damage) treatments (no DSS, 3% DSS, or DSS withdrawal). Fish oil feeding resulted in lower 8-OHdG levels (P = 0.038), higher levels of apoptosis (P = 0.035), and a lower cell proliferative index (P = 0.05) compared with corn oil feeding. In the top third of the crypt, fish oil caused an incremental stimulation of apoptosis with increased DNA damage (P = 0.043), whereas there was no such relationship with corn oil. Because polyps and tumors develop from DNA damage that leads to loss of growth and death control, the significant difference in fish oil vs. corn oil on these variables may account, in part, for the observed protective effect of fish oil against oxidatively induced colon cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • Minimal processing was required to fabricate a wound healing scaffold from soft-shell crab carapace. • The carapace has small prickles that improves cell adhesion and guide cell migration. • Epidermis-dermis reattachment was accelerated, and wound topography improved upon scaffold application. A chitin wound healing membrane was extracted and minimally processed from soft-shell crab carapace, a fabrication method simpler than the conventional process of chemically modifying chitin into more soluble and bioactive derivatives. We observed an interesting difference between the topography of the membrane's internal and external surface, which correlated with their different abilities to promote cell adhesion and proliferation. The internal surface was dotted with prickles where cells could adhere and elongate, while the smooth external surface demonstrated poor cell adhesion and proliferation. Applying the internal surface of the membrane onto the wound improved the epidermis surface homogeneity and accelerated epidermis-dermis re-attachment. This membrane also showed an excellent tensile strength of 105.7 ± 29.9 MPa and ultimate strain of 6.5 ± 4.2%, higher than those of common wound healing membranes from cellulose, and collagen. These results showed the ability of chitin membranes from soft-shell crab carapaces to support cell attachment, proliferation, and migration and its potential for further wound healing applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is the most common form of primary malignant brain tumor with a devastatingly poor prognosis. Tumor heterogeneity (cellular, molecular and immune) is the major obstacle to current treatment failure. We revisited the recent literature to understand the heterogeneous features of GBM and their potential role in treatment resistance. This review provides a comprehensive overview covering the GBM's pathogenetic features, currently available treatment options and the treatments currently under development in the clinic. Glioblastoma (GBM) is the most common form of primary malignant brain tumor with a devastatingly poor prognosis. The disease does not discriminate, affecting adults and children of both sexes, and has an average overall survival of 12–15 months, despite advances in diagnosis and rigorous treatment with chemotherapy, radiation therapy, and surgical resection. In addition, most survivors will eventually experience tumor recurrence that only imparts survival of a few months. GBM is highly heterogenous, invasive, vascularized, and almost always inaccessible for treatment. Based on all these outstanding obstacles, there have been tremendous efforts to develop alternative treatment options that allow for more efficient targeting of the tumor including small molecule drugs and immunotherapies. A number of other strategies in development include therapies based on nanoparticles, light, extracellular vesicles, and micro-RNA, and vessel co-option. Advances in these potential approaches shed a promising outlook on the future of GBM treatment. In this review, we briefly discuss the current understanding of adult GBM's pathogenetic features that promote treatment resistance. We also outline novel and promising targeted agents currently under development for GBM patients during the last few years with their current clinical status. [ABSTRACT FROM AUTHOR]

Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 different IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an efficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential efficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic effects of OHSV-IL12 as mono- and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy. [ABSTRACT FROM AUTHOR]