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The immune system eliminates advanced cancer when treated with programmed cell death protein-1 (PD-1) or its ligand (PD-L1) blockade, but PD-1 therapy is effective in only ∼20% of patients with solid cancer. The PD-1 antibody mainly acts on the effector phase of cytotoxic T lymphocytes (CTLs) in tumors but induces no activation of the priming phase of antigen-presenting dendritic cells (DCs). It is reasonable that both DC-priming and PD-1/L1 blocking are mandatory for efficient CTL-mediated tumor cytolysis. For DC-priming, a therapeutic vaccine containing Toll-like receptor (TLR) agonists, namely a priming adjuvant, is a good candidate; however, a means for DC-targeting by TLR adjuvant therapy remains to be developed. TLR adjuvants usually harbor cytokine toxicity, which is a substantial barrier against drug approval. Here, we discuss the functional properties of current TLR adjuvants for cancer immunotherapy and introduce a TLR3-specific adjuvant (ARNAX) that barely induces cytokinemia in mouse models.

Cancer vaccines consist of a tumor-associated antigen (TAA) and adjuvant. These vaccines induce and activate proliferation of TAA-specific cytotoxic T lymphocytes (CTLs), suppressing tumor growth. The therapeutic efficacy of TAA-specific CTLs depends on the properties of tumor microenvironment. The environments make immunosuppressive by function of regulatory T cells and tumor-associated myeloid cells; thus, regulation of these cells is important for successful cancer immunotherapy. We report here that L-ergothioneine (EGT) with the adjuvant Toll-like receptor 2 (TLR2) ligand modulated suppressive microenvironments to be immune-enhancing. EGT did not augment DC-mediated CTL priming or affect CTL activation in draining lymph node and spleen. However, EGT decreased the immuno-suppressive function of tumor-associated macrophages (TAMs). TLR2 stimulation accompanied with EGT administration downregulated expression of PD-L1, CSF-1R, arginase-1, FAS ligand, and TRAIL in TAMs, reflecting reduction of CTL suppression. An anti-oxidative thiol-thione residue of EGT was essential to dampening CTL suppression. The effect was specific to the thiol-thione residue of EGT because no effect was observed with another anti-oxidant N-acetyl-L-cysteine (NAC). A CTL-suppressive environment made by TLR2 is relieved to be improved by the addition of EGT, which may ameliorate the efficacy of vaccine immunotherapy.

L-Ergothioneine (EGT) is a naturally-occurring amino acid which is characterized by its antioxidant property; yet, the physiological role of EGT has yet to be established. We investigated the immune-enhancing properties of EGT, and found that it acts as a potentiator of toll-like receptor (TLR) signaling. When mouse bone marrow-derived macrophages (BMDMs) were pretreated with EGT, TLR signal-mediated cytokine production was augmented in BMDMs. The results were reproducible with TLR2, 3, 4 and 7 agonists. In particular, IL-6 and IL-12p40 were elevated further by pretreatment with EGT in BMDMs, suggesting the induction of M1 polarization. In co-culture assay with OT-II CD4+ T cells and splenic F4/80+ macrophages, EGT significantly induced Th17 skewing in CD4+ T cells. Thus, EGT is an immune modifier as well as a redox controller under TLR stimulation that induces M1 macrophages and a Th17 shift in inflammation.

Immunological checkpoint blockade therapies benefit a limited population of cancer patients. We have previously shown that vaccine immunotherapy with Toll‐like receptor (TLR)3‐adjuvant and tumor antigen overcomes anti‐programmed death ligand‐1 (PD‐L1) resistance in mouse tumor models. In the present study, 4 different ovalbumin (OVA)‐expressing tumor cell lines were implanted into syngeneic mice and subjected to anti‐tumor immunotherapy using ARNAX and whole OVA protein. ARNAX is a TLR3‐specific agonist that does not activate the mitochondrial antiviral‐signaling protein (MAVS) pathway, and thus does not induce systemic inflammation. Dendritic cell priming and proliferative CTL were induced by ARNAX + OVA, but complete remission was achieved only in a PD‐L1‐low cell line of EG7. Addition of anti‐PD‐L1 antibody to the ARNAX + OVA therapy brought complete remission to another PD‐L1‐high subline of EG7. Tumor shrinkage but not remission was observed in MO5 in that regimen. We analyzed tumor cells and tumor‐infiltrating immune cells to identify factors associated with successful ARNAX vaccine therapy. Tumors that responded to ARNAX therapy expressed high levels of MHC class I and low levels of PD‐L1. The tumor‐infiltrating immune cells in ARNAX‐susceptible tumors contained fewer immunosuppressive myeloid cells with low PD‐L1 expression. Combination with anti‐PD‐L1 antibody functioned not only within tumor sites but also within lymphoid tissues, augmenting the therapeutic efficacy of the ARNAX vaccine. Notably, ARNAX therapy induced memory CD8+ T cells and rejection of reimplanted tumors. Thus, ARNAX vaccine + anti‐PD‐L1 therapy enabled permanent remission against some tumors that stably present antigens. TLR3‐specific adjuvant ARNAX + TAA induces dendritic cell priming and proliferative cytotoxic T lymphocytes (CTL). Tumor‐specific memory CTL are generated in ARNAX‐sensitive tumors, and they inhibit tumor growth of reimplanted tumors.

Radiotherapy induces anti‐tumor immunity by induction of tumor antigens and damage‐associated molecular patterns (DAMP). DNA, a representative DAMP in radiotherapy, activates the stimulator of interferon genes (STING) pathway which enhances the immune response. However, the immune response does not always parallel the inflammation associated with radiotherapy. This lack of correspondence may, in part, explain the radiation‐resistance of tumors. Additive immunotherapy is expected to revive tumor‐specific CTL facilitating radiation‐resistant tumor shrinkage. Herein pre‐administration of the double‐stranded RNA, polyinosinic‐polycytidylic acid (polyI:C), in conjunction with radiotherapy, was shown to foster tumor suppression in mice bearing radioresistant, ovalbumin‐expressing Lewis lung carcinoma (LLC). Extrinsic injection of tumor antigen was not required for tumor suppression. No STING‐ and CTL‐response was induced by radiation in the implant tumor. PolyI:C was more effective for induction of tumor growth retardation at 1 day before radiation than at post‐treatment. PolyI:C targeted Toll‐like receptor 3 with minimal effect on the mitochondrial antiviral‐signaling protein pathway. Likewise, the STING pathway barely contributed to LLC tumor suppression. PolyI:C primed antigen‐presenting dendritic cells in draining lymph nodes to induce proliferation of antigen‐specific CTL. By combination therapy, CTL efficiently infiltrated into tumors with upregulation of relevant chemokine transcripts. Batf3‐positive DC and CD8+ T cells were essential for therapeutic efficacy. Furthermore, polyI:C was shown to stimulate tumor‐associated macrophages and release tumor necrosis factor alpha, which acted on tumor cells and increased sensitivity to radiation. Hence, polyI:C treatment prior to radiotherapy potentially induces tumor suppression by boosting CTL‐dependent and macrophage‐mediated anti‐tumor responses. Eventually, polyI:C and radiotherapy in combination would be a promising therapeutic strategy for radiation‐resistant tumors. TLR3‐adjuvant (polyI:C) immunotherapy in combination with radiotherapy facilitates proliferating tumor‐specific cytotoxic T cells to regress radiation‐resistant tumor in mouse models. Tumor microenvironment would be an additional target of polyI:C to evoke anti‐tumor immunity.

Stable iodine tablets are effective in reducing internal exposure to radioactive iodine, which poses a risk for thyroid cancer and other conditions. After the Fukushima Daiichi nuclear power plant accident, the Japanese government shifted its policy on stable iodine tablet distribution from “after-the-fact” to “before-the-fact” and instructed local governments to pre-distribute stable iodine tablets to residents living within a 5-km radius of nuclear facilities. The nation’s first pre-distribution of stable iodine tablets was carried out in June and July of 2014 in Kagoshima Prefecture. Health surveys were conducted so that the medication would not be handed out to people with the possibility of side effects. Of the 4715 inhabitants in the area, 132 were found to require a physician’s judgment, mostly to exclude risks of side effects. This was considered important to prevent the misuse of the tablets in the event of a disaster. The importance of collective and individualized risk communication between physicians and inhabitants at the community health level was apparent through this study. Involvement of physicians through the regional Sendai City Medical Association was an important component of the pre-distribution. Physicians of the Sendai City Medical Association were successfully educated by using the Guidebook on Distributing and Administering Stable Iodine Tablets prepared by the Japan Medical Association and Japan Medical Association Research Institute with the collaboration of the National Institute of Radiological Sciences and the Japanese government. Thus, the physicians managed to make decisions on the dispensing of stable iodine tablets according to the health conditions of the inhabitants. All physicians nationwide should be provided continuing medical education on stable iodine tablets. (Disaster Med Public Health Preparedness. 2017;11:365–369)

Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway. We established Apc Ticam1 mice and their survival was compared to survival of Apc Myd88 and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis. We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc background. Polyps were more frequently formed in the distal intestine of Apc Ticam1 mice than in Apc mice. Infiltration of immune cells such as CD11b and CD8α cells into the polyps was detected histologically. CD11b and CD8α mRNAs were increased in polyps of Apc Ticam1 mice compared to Apc mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc Ticam1 mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc Ticam1 mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc mice. These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc mice.

Iwate, Miyagi, Fukushima, and Ibaraki. 1 After the Great East Japan Earthquake in 2011, the JMA, as the professional society of Japanese physicians, recognized the importance of incorporating foreign medical teams (FMTs) into its large-scale disaster response efforts. 2 The JMA has developed international medical teams of the JMA, or iJMAT, as a new framework to accept FMTs to provide medical care in the event of major disasters, particularly the predicted Tokyo metropolitan or South Sea Thrust mega-earthquakes. 3 The main aim of the iJMAT program is to secure the quality of care provided and certification of physicians’ qualifications to meet the needs of disaster-affected areas. The World Medical Association Declaration of Montevideo, 4 adopted in October 2011, calls upon its members “to promote a standard competency set to ensure consistency among disaster training programs for physicians across all specialties.” The Sphere Project was initiated in 1997 by a group of nongovernmental organizations and the Red Cross and Red Crescent Movement to develop a set of universal, minimum standards in core areas of humanitarian responses, resulting in creation of the Sphere Handbook. 5 Based on lessons learned through successful deployment of JMATs and difficulties in accepting FMTs following the Great East Japan Earthquake, the concept of international medical teams in the JMAT was proposed by the JMA.

Background Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc Min/+ mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway. Methods We established Apc Min/+ Ticam1 −/− mice and their survival was compared to survival of Apc Min/+ Myd88 −/− and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis. Results We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc Min/+ mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc Min/+ background. Polyps were more frequently formed in the distal intestine of Apc Min/+ Ticam1 −/− mice than in Apc Min/+ mice. Infiltration of immune cells such as CD11b + and CD8α + cells into the polyps was detected histologically. CD11b and CD8α mRNAs were increased in polyps of Apc Min/+ Ticam1 −/− mice compared to Apc Min/+ mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc Min/+ Ticam1 −/− mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc Min/+ Ticam1 −/− mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc Min/+ mice. Conclusion These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc Min/+ mice.

Sound localization is essential for auditory spatial awareness. The process relies on interaural differences in timing and level, and spectral cues. This study aimed to standardize sound-localization testing conditions across facilities in Japan, analyze the impact of early reflected sounds on localization accuracy, and compare outcomes between individuals with normal hearing and those with unilateral hearing loss. This study included 77 participants with normal hearing and 45 individuals with unilateral hearing loss, at 11 facilities. Sound-localization tests were conducted using nine loudspeakers arranged in a 180° horizontal arc. The stimuli consisted of Comité Consultatif International Téléphonique et Télégraphique (CCITT) and low-pass CCITT noise bursts at randomized levels of 50, 55, and 60 dB SPL. The reflected sound measurements employed time-stretched pulses to analyze early reflections (4–7 ms). The localization accuracy was assessed using the root-mean-square error and mean deviation score. Localization performance was negatively influenced by early reflections, with reflected sound envelope area and peak values within 4–7 ms correlating significantly with reduced accuracy (r = −0.535 to −0.555). Participants with normal hearing achieved a root-mean-square error of 2.0° ± 4.8°, whereas participants with unilateral hearing loss exhibited significantly greater errors (68.4° ± 40.7°, p < .001). Asymmetries in the left–right response accuracy correlated positively with the reflected sound characteristics (r > 0.6). Noise type (normal vs. low-pass CCITT) did not significantly impact performance in either group. Early reflections significantly compromise sound-localization accuracy, particularly in smaller testing environments where reflections overlap with direct sounds. Standardized testing protocols, in which early reflections are controlled, are critical for reliable assessments. The use of sound-absorbing materials can enhance the test precision, particularly in the clinical evaluation of unilateral hearing loss. These findings emphasize the need for optimizing acoustic conditions to improve the reliability and accuracy of sound-localization testing.