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...

Single-walled carbon nanotube (SWNT) rings have been synthesized via the noncovalent hybridization of carbon nanotubes and porphyrins. Optical absorption spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) results showed that the formation of the SWNT rings is strongly affected by the molecular architecture of the porphyrins, the hybrid concentration, the SWNT-to-porphyrin mass ratio, and the substrate on which the hybrid films were coated. We found that the SWNT hybrid rings result from the formation of porphyrin J-aggregates on the outer surfaces of the SWNTs and the tendency of porphyrins to aggregate in wheel structures. We also demonstrated that electron donation by the substituent groups in the para-positions of the phenyl rings in 5,10,15,20-tetraphenyl-21H,23H-phorphine (TPP) and the structural regularity of the substituent groups facilitate the formation of J-aggregates of the TPP derivatives. This novel method presents new theoretical challenges and potentially provides a simple approach based on the noncovalent hybridization of porphyrins and SWNTs to the synthesis of SWNT superstructures.

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.

Highly accumulated hyaluronan (HA) not only provides a physiological barrier but also supports an immune‐suppressive tumour microenvironment. High‐molecular‐weight (HMW)‐HA inhibits the activation of immune cells and their access into tumour tissues, whereas, low‐molecular‐weight oligo‐HA is known to potentially activate dendritic cells (DCs). In this paper, we investigated whether small extracellular vesicle (EVs)‐PH20 hyaluronidase induces tumour HA degradation, which, in turn, activates DCs to promote anti‐cancer immune responses. Informed by our previous work, we used a small EV carrying GPI‐anchored PH20 hyaluronidase (Exo‐PH20) that could deeply penetrate into tumour foci via HA degradation. We found that Exo‐PH20‐treatment successfully activates the maturation and migration of DCs in vivo, particularly CD103+ DCs leading to the activation of tumour‐specific CD8+ T cells, which work together to inhibit tumour growth. Moreover, combination with anti‐PD‐L1 antibody provided potent tumour‐specific CD8+ T cell immune responses as well as elicited prominent tumour growth inhibition both in syngenic and spontaneous breast cancer models, and this anti‐tumour immunity was durable. Together, these results present new insights for HA degradation by Exo‐PH20, providing a better understanding of oligo HA‐triggered immune responses to cancer.

We derive relations between the Aharonov invariants and Tamanoi's Schwarzian derivatives of higher order and give a recursive formula for Tamanoi's Schwarzians. Then we propose a definition of invariant Schwarzian derivatives of a nonconstant holomorphic map between Riemann surfaces with conformal metrics. We show a recursive formula also for our invariant Schwarzians.

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Cancer immunotherapy is fast rising as a prominent new pillar of cancer treatment, harnessing the immune system to fight against numerous types of cancer. Rho-kinase (ROCK) pathway is involved in diverse cellular activities, and is therefore the target of interest in various diseases at the cellular level including cancer. Indeed, ROCK is well-known for its involvement in the tumor cell and tumor microenvironment, especially in its ability to enhance tumor cell progression, migration, metastasis, and extracellular matrix remodeling. Importantly, ROCK is also considered to be a novel and effective modulator of immune cells, although further studies are needed. In this review article, we describe the various activities of ROCK and its potential to be utilized in cancer treatment, particularly in cancer immunotherapy, by shining a light on its activities in the immune system.