Cancer immunotherapy including vaccine therapy is a promising modality for cancer treatment, but few patients show its clinical benefits currently. The identification of biomarkers that can identify patients who will benefit from cancer immunotherapy is thus important. Here, we investigated the potential utility of the circulating cell-free DNA (cfDNA) integrity-a ratio of necrotic cell-derived, longer DNA fragments versus apoptotic cell-derived shorter fragments of Alu gene-as a biomarker of vaccine therapy for patients with ovarian cancer. We analyzed plasma samples from 39 patients with advanced or recurrent ovarian cancer enrolled in clinical trials for personalized peptide vaccinations. We observed that (1) the cfDNA integrity was decreased after the first cycle of vaccination, and (2) the decreased levels of cfDNA integrity were correlated with vaccine-induced immune responses; i.e., decreased cfDNA integrity was observed in 91.7% and 59.3% of the IgGpositive and negative patients, respectively (p = 0.0445). Similarly, decreased cfDNA integrity was observed in 92.9% and 56.0% of CTL response-positive and negative patients, respectively (p = 0.0283). These results suggest that the circulating cfDNA integrity is a possible biomarker for cancer vaccine therapy.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

High mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that 1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, 2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and 3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called “cold” to “immune-inflamed” or “hot” and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.

High-mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that (1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, (2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and (3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called “cold” to “immune-inflamed” or “hot” and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.

Severe fever with thrombocytopenia syndrome (SFTS) is an infection mediated by ticks and has been reported to have a high mortality rate in Japan. At our hospital, we reported three cases of SFTS with relatively positive outcomes. We reviewed reports of SFTS cases in Japan to clarify the current state of the disease in Japan, the treatment provided, and its outcome. The Ichushi Web was searched for literature using the following terms as keywords: “SFTS” or “severe fever with thrombocytopenia syndrome”. Overall, 174 cases were collected and reviewed. The mean age of patients was 70.69 years old, and the mortality rate was 35%. The dead group was significantly older (p < 0.001) than the alive group, had a significantly shorter period from symptom onset to hospital admission, and experienced significantly more hemorrhage-related and neurological symptoms. Further, the most frequently provided treatment methods were adrenocorticosteroids, antibiotics, and conservative treatment. The low recognition rate of SFTS in Japan might lead to a misdiagnosis or delay in diagnosis and treatment, especially in mild to moderate cases. Medical professionals and citizens who live in areas inhabited by ticks need to be informed about SFTS to appropriately diagnose and manage SFTS cases in Japan in the future.

Background: Many clinical trials of immune checkpoint blockade-based combination therapies are under way. Vaccine therapy is a promising partner of combination therapies. We have developed a personalized peptide vaccination and conducted clinical trials of it in patients with various cancers. At the present time, we have only a limited number of biomarkers related to the prognosis of vaccinetreated patients. Thus, new biomarkers are urgently needed. Methods: In this study, we investigated the plasma cell-free DNA (cfDNA) integrity-a ratio of the necrotic tumor cell-derived long cfDNA fragments to the total dead cell-derived short cfDNA fragments from genomic Alu elements-in patients with advanced nonsmall cell lung cancer during treatment with the personalized peptide vaccination. Results: We found that (1) the cfDNA integrity was decreased after the first cycle of vaccination, and (2) the patients with high prevaccination cfDNA integrity survived longer than those with low prevaccination integrity (median survival time (MST): 17.9 versus 9.0 months, respectively; hazard ratio (HR): 0.58, p ¼ .0049). A similar tendency was observed in postvaccination cfDNA integrity (MST: 16.4 vs 9.4 months; HR: 0.65, p ¼ .024). Conclusions: These results suggest that cfDNA integrity is a possible prognostic biomarker in patients treated with the personalized peptide vaccine.