remains unclear how and why cancer occurs and progresses. Using an evolutionary approach, the concept of a complex adaptive system (CAS) was developed to describe the behaviors of cancer tumorigenesis, [2] which may suggest a frameshift away from the limitations of current approaches that mainly address the importance of alteration in specific target molecules in cancer cells. This change in perspectives toward tumors, not simply as a disease to be cured but also as CAS, is expected to be the cornerstone of the paradigm shift toward innovative cancer therapies. [3] The human immune system can also be viewed as a CAS and therefore expected to initiate self-defense mechanisms against cancer in a complex adaptive manner as long as it recognizes the cancer cells as the non-self-signals. Consequently, the key to controlling cancer could lie in understanding how to manipulate the immune system and strengthen its defenses against cancer. The concept of facilitating the immune system to fight against cancer was first suggested in the late 1800s by Dr. Wiliam Coley, who was the first to observe anti-tumor effects after intratumoral injection of microbe-derived toxins. [4] Since then, the field of cancer immunotherapy research has flourished, resulting in clinical achievements such as immune checkpoint blockades and chimeric antigen receptor T cell (CAR-T) therapy. [5] However, immune suppression resistance mechanisms have simultaneously been identified that have impeded favorable response to cancer immunotherapy. [6,7] Exosome-based cancer therapies have emerged as a potential option for overcoming these limitations to the effects of current cancer therapies due to their pathophysiological efficacy against tumors. [8] Exosomes are secreted externally by cells and are found ubiquitously in blood, urine, saliva, cerebrospinal fluid, pleural fluid, and breast milk. [9,10] The distinction between different types of extracellular vesicles (EVs) is unclear; however, they are conventionally classified as either ectosomes (microvesicles or microparticles) or exosomes. [11] While ectosomes are formed by the outward budding of the plasma membrane, exosomes are formed from multivesicular bodies (MVB) containing intraluminal vesicles via inward budding of the late endosome, which later fuses to the membrane. The formed vesicles are then secreted via a process known as exocytosis (Figure 1). The two types of vesicle also differ in diameter, Exosomes are a class of extracellular vesicles of around 100 nm in diameter that are secreted by most cells and contain various bioactive molecules reflecting their cellular origin and mediate intercellular communication. Studies of these exosomal features in tumor pathogenesis have led to the development of therapeutic and diagnostic approaches using exosomes for cancer therapy. Exosomes have many advantages for conveying therapeutic agents such as small interfering RNAs, microRNAs, membrane-associated proteins, and chemotherapeutic compounds; thus, they are considered a prime candidate as a deliv...

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Activation of T cell immune response is critical for the therapeutic efficacy of cancer immunotherapy. Current immunotherapies have shown remarkable clinical success against several cancers; however, significant responses remain restricted to a minority of patients. Here, we show a therapeutic strategy that combines enhancing the phagocytic activity of antigen-presenting cells with immunogenic cell death to trigger efficient antitumour immunity. Rho-kinase (ROCK) blockade increases cancer cell phagocytosis and induces antitumour immunity through enhancement of T cell priming by dendritic cells (DCs), leading to suppression of tumour growth in syngeneic tumour models. Combining ROCK blockade with immunogenic chemotherapy leads to increased DC maturation and synergistic CD8+ cytotoxic T cell priming and infiltration into tumours. This therapeutic strategy effectively suppresses tumour growth and improves overall survival in a genetic mouse mammary tumour virus/Neu tumour model. Collectively, these results suggest that boosting intrinsic cancer immunity using immunogenic killing and enhanced phagocytosis is a promising therapeutic strategy for cancer immunotherapy.

BackgroundUveal melanoma (UM) is the most frequent intraocular malignancy and is resistant to immunotherapy. Nearly 50% of patients with UM develop metastatic disease, and the overall survival outcome remains very poor. Therefore, a treatment regimen that simultaneously targets primary UM and prevents metastasis is needed. Here, we suggest an immunotherapeutic strategy for UM involving a combination of local photodynamic therapy (PDT), rho-kinase (ROCK) inhibitor, and PD-1/PD-L1 immune checkpoint blockade.MethodsThe antitumor efficacy and immune response of monotreatment or combinational treatment were evaluated in B16F10-bearing syngeneic mouse models. Abscopal antitumor immune responses induced by triple-combinational treatment were validated in syngeneic bilateral B16F10 models. After each treatment, the immune profiles and functional examinations were assessed in tumors and tumor draining lymph nodes by flow cytometry, ELISA, and immunofluorescence assays. In orthotopic intraocular melanoma models, the location of the immune infiltrate in the tumor microenvironment (TME) was evaluated after each treatment by multiplex immunohistochemistry and metastatic nodules were monitored.ResultsPDT with Ce6-embedded nanophotosensitizer (FIC-PDT) elicited immunogenic cell death and stimulated antigen-presenting cells. In situ immunogenic clearance induced by a combination of FIC-PDT with ripasudil, a clinically approved ROCK inhibitor, stimulated antigen-presenting cells, which in turn primed tumor-specific cytotoxic T cells. Moreover, local immunogenic clearance sensitized PD-1/PD-L1 immune checkpoint blockade responses to reconstruct the TME immune phenotypes of cold tumors into hot tumors, resulting in recruitment of robust cytotoxic CD8+ T cells in the TME, propagation of systemic antitumor immunity to mediate abscopal effects, and prolonged survival. In an immune-privileged orthotopic intraocular melanoma model, even low-dose FIC-PDT and ripasudil combined with anti-PD-L1 antibody reduced the primary tumor burden and prevented metastasis.ConclusionsA combination of localized FIC-PDT and a ROCK inhibitor exerted a cancer vaccine-like function. Immunogenic clearance led to the trafficking of CD8+ T cells into the primary tumor site and sensitized the immune checkpoint blockade response to evoke systemic antitumor immunity to inhibit metastasis, one of the major challenges in UM therapy. Thus, immunogenic clearance induced by FIC-PDT and ROCK inhibitor combined with anti-PD-L1 antibody could be a potent immunotherapeutic strategy for UM.

BackgroundStatins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.MethodsThe immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.ResultsStatin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.ConclusionsOur findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.

We developed and characterized a novel in situ chitosan-poly(ethylene oxide) (PEO) hydrogel via two steps: 2-carboxyethyl acrylate molecules were grafted to the primary amine functional groups in chitosan in the first step and then Michael type addition reaction was processed between the grafted acrylate end groups and the thiol end groups in the PEO. Grafting of acrylate molecules to the amine groups in the deacetylated water soluble chitosan was confirmed by observing the new acrylate peaks by the FTIR and NMR spectra of the acrylated chitosan samples, as well as changes in relative viscosities of chitosan and acrylated chitosan. Formation of the chitosan-PEO hydrogel was visually observed with digital images after both gelation and hydration. Rheological analyses of the hydrogel formation were performed to detect its gelation time, phase angle changes, and visco-elastic properties over frequency and strain percentage. Their results indicated that the gelation process was completed within 10 min after mixing the precursor liquid solutions. An extent of water swelling, mechanical strength against compression and the morphologies of the hydrogel surface and cross sections after dehydration process were analyzed by microbalance measurement, texture analyzer, and scanning electron microscopy observation, respectively. Biological activities of the hydrogels were evaluated by observing smooth muscle cell behaviors such as cell adhesion and viability as well as by measuring the number of adhered cells on their surfaces.

Sustainable agriculture in the era of climate change needs to find solutions for the retention and proper utilization of water. This study proposes an ensemble approach for identifying the virtual water content (VWC) of main crops on the Korean Peninsula in past and future climates. Ensemble results with low uncertainty were obtained using three regional climate models, five potential evapotranspiration methods, and the Environmental Policy Integrated Climate (EPIC) crop model. The productivity results of major crops (rice and maize) under climate change are likely to increase more than in the past based on the ensemble results. The ensemble VWC is calculated using three types of crop yields and fifteen consumptive amounts of water use in the past and the future. While the ensemble VWC of rice and maize was 1.18 m 3 kg −1 and 0.58 m 3 kg −1 , respectively, in the past, the future amounts were estimated at 0.76 m 3 kg −1 and 0.48 m 3 kg −1 , respectively. The yields of both crops showed a decline in future projections, indicating that this change could have a positive impact on future water demand. The positive changes in crop productivity and water consumption due to climate change suggest that adaptation to climate change can be an opportunity for enhancing sustainability as well as for minimizing agricultural damage.