Azusa Terasaki

All Publications

• Mitochondrial transfer from immune to tumor cells enables lymph node metastasis. Cell metabolism Terasaki, A., Bhatnagar, K., Weiner, A. T., Tan, Y., Szeifert, V., Huang, H. L., Wiggers, L., Rodrigues, V., Rada, C. C., Shankar, V., Saito, S., Ankomah, P. O., Roth, T., Chiu, B., West, R., Li, L., Reticker-Flynn, N., Axelrod, J. D., Brestoff, J. R., Li, B., Engleman, E., Okwan-Duodu, D. 2026

  Abstract

  Although the immune system is a significant barrier to tumor growth and spread, established tumors evade immune attack and frequently colonize immune populated areas such as the lymph node. The mechanisms by which cancer cells subvert the tumor-immune microenvironment to favor spread to the lymph node remain incompletely understood. Here, we show that, as a common attribute, tumor cells hijack mitochondria from a wide array of immune cells. Mitochondria loss by immune cells decreases antigen-presentation and co-stimulatory machinery, as well as reducing the activation and cytotoxic capacity of natural killer (NK) and CD8 T cells. In cancer cells, the exogenous mitochondria fuse with endogenous mitochondria networks, leak mtDNA into the cytosol, and stimulate cGAS/STING, activating type I interferon-mediated immune evasion programs. Blocking mitochondrial transfer machinery-including cGAS, STING, or type I interferon-reduced cancer metastasis to the lymph node. These findings suggest that cancer cells leverage mitochondria hijacking to weaken anti-tumor immunosurveillance and use the acquired mitochondria to fuel the immunological requirements of lymph node colonization.

  View details for DOI 10.1016/j.cmet.2025.12.014

  View details for PubMedID 41529696

• Mitochondria redistribution organizes the immunosuppressive tumor ecosystem. bioRxiv : the preprint server for biology Terasaki, A., Weiner, A. T., Tan, Y., Szeifert, V., Bhatnagar, K., Rada, C. C., Shankar, V., Kernick, C., Mahmood, M., Wiggers, L., Rodrigues, V. R., Gammage, P. A., Roth, T., Axelrod, J. D., Engleman, E., Li, B., Okwan-Duodu, D. 2025

  Abstract

  Hostile conditions in the tumor microenvironment restrict cellular respiration, yet mitochondrial metabolism remains indispensable for tumor growth and the activity of immunosuppressive cells. How tumor ecosystems sustain mitochondrial output has been unclear. Here, we show that cancer cells resolve this paradox by acting as hubs of intercellular mitochondrial redistribution. Using mitochondrial reporter systems, we demonstrate that cancer cells import host-derived mitochondria, integrate them into their endogenous network, and subsequently relay these hybrid organelles to neighboring immune cells. Mitochondria redistribution reprograms recipient neutrophils, macrophages, and CD4⁺ T cells into highly suppressive states but drives CD8⁺ T cell exhaustion. Within cancer cells, fusion of incoming mitochondria induces filamentous P5CS assembly, enhances biosynthetic output, and enables the refurbishment of damaged organelles into fully functional units. Disrupting mitochondrial redistribution collapses the immunosuppressive ecosystem and impairs tumor growth. Thus, cancer cells do not hoard resources but orchestrate a redistribution program that fortifies their own metabolic resilience, derails anti-tumor immunity, and sustains immunosuppressive partners.

  View details for DOI 10.1101/2025.11.11.687895

  View details for PubMedID 41292779

  View details for PubMedCentralID PMC12642609

• When Central Tolerance Fails: Thymic Malignancies at the Intersection of Cancer Immunity and Autoimmunity. Cancers Abikenari, M., Choi, J., Enayati, I., Tucker, A., Bhatnagar, K., Chen, Y., Himic, V., Liu, J., Nageeb, G., Poe, J., Ong, S. J., Sanker, V., Diehl, M., Szeifert, V., Terasaki, A., Prolo, L. M., Engleman, E., Okwan-Duodu, D. 2026; 18 (5)

  Abstract

  Thymic malignancies are rare cancers arising from thymic epithelial cells and are characterized by a highly diverse clinical phenotype, substantial histologic and morphologic heterogeneity, and frequent associations with autoimmune syndromes. Although the clinical, immunological, and cytoarchitectural changes associated with thymomas have been increasingly elucidated in the contemporary literature, very few studies have interrogated the direct role of tumor staging and histological grading in shaping autoimmunity burden and infection risk. In this narrative review, we synthesize contemporary clinical, immunological, and morphologic evidence linking thymic architecture and selection defects to the spectrum of paraneoplastic autoimmunity (MG, pure red cell aplasia, Good's syndrome) and to infectious vulnerability. We further appraise emerging therapeutic strategies, including immune checkpoint inhibition and adoptive cellular approaches, through a patient-stratified lens, emphasizing efficacy signals, immune-related adverse events, and practical considerations for selection and monitoring. We conclude by highlighting priorities for future investigation, including refining autoantibody signatures; mapping thymic microenvironments that drive tolerance failure, and prospectively evaluating stratified immunotherapeutic regimens that balance benefit with immune-mediated risk.

  View details for DOI 10.3390/cancers18050747

  View details for PubMedID 41827683

• Neutrophils Expressing Programmed Death-Ligand 1 Play an Indispensable Role in Effective Bacterial Elimination and Resolving Inflammation in Methicillin-Resistant Staphylococcus aureus Infection. Pathogens (Basel, Switzerland) Terasaki, A., Ahmed, F., Okuno, A., Peng, Z., Cao, D. Y., Saito, S. 2024; 13 (5)

  Abstract

  Programmed death ligand 1 (PD-L1) is a co-inhibitory molecule expressed on the surface of various cell types and known for its suppressive effect on T cells through its interaction with PD-1. Neutrophils also express PD-L1, and its expression is elevated in specific situations; however, the immunobiological role of PD-L1+ neutrophils has not been fully characterized. Here, we report that PD-L1-expressing neutrophils increased in methicillin-resistant Staphylococcus aureus (MRSA) infection are highly functional in bacterial elimination and supporting inflammatory resolution. The frequency of PD-L1+ neutrophils was dramatically increased in MRSA-infected mice, and this population exhibited enhanced activity in bacterial elimination compared to PD-L1- neutrophils. The administration of PD-L1 monoclonal antibody did not impair PD-L1+ neutrophil function, suggesting that PD-L1 expression itself does not influence neutrophil activity. However, PD-1/PD-L1 blockade significantly delayed liver inflammation resolution in MRSA-infected mice, as indicated by their increased plasma alanine transaminase (ALT) levels and frequencies of inflammatory leukocytes in the liver, implying that neutrophil PD-L1 suppresses the inflammatory response of these cells during the acute phase of MRSA infection. Our results reveal that elevated PD-L1 expression can be a marker for the enhanced anti-bacterial function of neutrophils. Moreover, PD-L1+ neutrophils are an indispensable population attenuating inflammatory leukocyte activities, assisting in a smooth transition into the resolution phase in MRSA infection.

  View details for DOI 10.3390/pathogens13050401

  View details for PubMedID 38787253

  View details for PubMedCentralID PMC11124513

• Safety and Efficacy of Compression Therapy to Prevent Chemotherapy-Induced Peripheral Neuropathy in Lower Extremities of Breast Cancer Patients: A Pilot Study. Cureus Okazaki, M., Bando, H., Terasaki, A., Ueda, A., Iguchi-Manaka, A., Mathis, B. J., Hara, H. 2024; 16 (5): e60998

  Abstract

  Background Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic adverse event for breast cancer patients receiving taxane antimitotic agents. We evaluated the effectiveness of compression therapy against CIPN in the lower extremities of breast cancer patients receiving taxanes. Methods Eligible patients scheduled for perioperative treatment with taxanes for early-stage breast cancer were enrolled. Each patient wore latex-free surgical gloves and compression socks, putting on two layers of each 15 minutes before the administration of taxanes and removing them 15 minutes after administration. Peripheral neuropathy (PN) was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The primary endpoint was the incidence of CTCAE version 4.0 grade 2 or higher CIPN in the lower extremities during the entire period of perioperative chemotherapy with taxanes. Results PN assessment by CTCAE in the lower extremities, the primary outcome, showed that 13.3% developed grade 2 sensory disturbances, and 8.3% developed grade 2 motor disturbances. The incidence of CTCAE grade 2 or higher PN in the hands was 26.7% for sensory disturbances and 13.3% for motor disturbances during the entire study period. No patient had grade 3 or higher PN. No adverse events due to compression therapy were observed. Conclusion Compression of the lower extremities with compression socks tended to reduce the incidence of CIPN compared to the general incidence. Compression therapy may help prevent the development of CIPN.

  View details for DOI 10.7759/cureus.60998

  View details for PubMedID 38910688

  View details for PubMedCentralID PMC11193973

• Doublet or Triplet Antiemetic Prophylaxis for Nausea and Vomiting Induced by Trastuzumab Deruxtecan: an Open-Label, Randomized, and Multicenter Exploratory Phase 2 Study. Journal of Cancer Iihara, H., Shimokawa, M., Bando, H., Niwa, Y., Mizuno, Y., Kawaguchi, Y., Kitahora, M., Murakami, A., Kawai, M., Ishida, K., Takeuchi, M., Ishihara, K., Iyoda, T., Nakada, T., Ogiso, A., Kojima, Y., Kumagai, F., Sawa, A., Mori, R., Higuchi, K., Furuta, T., Kamei, Y., Tsuchiya, M., Terasaki, A., Yamamoto, S., Kitazawa, M., Okazaki, M., Suzuki, A., Futamura, M. 2023; 14 (14): 2644-2654

  Abstract

  Background: Trastuzumab deruxtecan is classified as an anticancer agent that poses a moderate emetic risk in the international guidelines for antiemetic therapy. The guidelines recommend emesis prophylaxis using a two-drug combination therapy comprising a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and dexamethasone (DEX). However, the high incidence of nausea and vomiting associated with trastuzumab deruxtecan is problematic. The National Comprehensive Cancer Network guideline version 1.2023 classified trastuzumab deruxtecan as having a high risk of emesis and changed its recommendation to a triplet regimen including a neurokinin-1 receptor antagonist (NK1RA). However, the emetogenic potential of trastuzumab-deruxtecan and the optimal antiemetic prophylaxis are controversial. Hence, this exploratory phase 2 study aimed to assess the efficacy and safety of treatment comprising 5-HT3RA and DEX with or without a NK1RA in preventing trastuzumab deruxtecan-induced nausea and vomiting. Methods: We conducted an open-label and randomized exploratory phase 2 study at 14 centers in Japan. Patients with breast cancer who were scheduled to receive trastuzumab deruxtecan were enrolled in this study. The patients were randomly assigned to receive granisetron and DEX (arm GD) or granisetron, DEX, and aprepitant (fosaprepitant; arm GDA). The primary endpoint was complete response (CR; no emesis or no rescue therapy) during the overall phase (120 h after the start of trastuzumab deruxtecan). Results: Between September 2020 and March 2023, 40 patients were randomly assigned to the GD (n = 19) or GDA (n = 21) arm. In the GDA arm, one patient who did not complete the use of the rescue medication listed in the diary was excluded from the efficacy analysis, which included the use of rescue medication. The CR rates during the overall phase were 36.8% and 70.0% in the GD and GDA arms, respectively (odds ratio 0.1334; 95% confidence interval [CI]: 0.0232-0.7672; P = 0.0190), with a difference of 33.2%. No grade 3 or 4 toxicity related to antiemetic therapy was observed. Conclusions: Patients receiving trastuzumab deruxtecan require triple therapy, including mandatory NK1RA administration.

  View details for DOI 10.7150/jca.87169

  View details for PubMedID 37779870

  View details for PubMedCentralID PMC10539399

• Local recurrence of breast cancer histologically resembling Paget disease presumably due to needle tract seeding: a case report. International cancer conference journal Terasaki, A., Bando, H., Ueda, A., Okazaki, M., Hashimoto, S., Iguchi-Manaka, A., Kondo, Y., Hara, H. 2023; 12 (2): 143-148

  Abstract

  Seeding of cancer cells along the needle tract during core needle biopsy is a well-known phenomenon, with a reported frequency of between 22 and 50% [Hoorntje et al. in Eur J Surg Oncol 30:520-525, 2004;Liebens et al. in Maturitas 62:113-123, 2009;Diaz et al. in AJR Am J Roentgenol 173:1303-1313, 1999;]. Local recurrence due to needle tract seeding is rare because the immune system eliminates the cancer cells in most cases. In addition, most local recurrences due to needle tract seeding occur as invasive carcinoma after diagnosis of invasive ductal carcinoma of the breast or mucinous carcinoma, and needle tract seeding due to noninvasive carcinoma is uncommon. We herein report a rare case of local breast cancer recurrence histologically resembling Paget disease, presumably due to needle tract seeding after core needle biopsy for diagnosis of ductal carcinoma in situ of the breast. After receiving a diagnosis of ductal carcinoma in situ, the patient underwent skin-sparing mastectomy and breast reconstruction with a latissimus dorsi musculocutaneous flap. The pathological study showed ER/PgR-negative ductal carcinoma in situ, and no postoperative radiation therapy or systemic therapy was administered. Six months after the surgery, the patient had a breast cancer recurrence histologically resembling Paget disease, presumably in the scar of her core needle biopsy. The pathological study showed Paget disease localized in the epidermis, no invasive carcinoma, and no lymph node metastasis. It was morphologically similar to the primary lesion and was diagnosed as a local recurrence due to needle tract seeding.

  View details for DOI 10.1007/s13691-023-00594-x

  View details for PubMedID 36896205

  View details for PubMedCentralID PMC9989070

• Absolute Lymphocyte Count as an Independent Prognostic Factor in Metastatic Breast Cancer: A Retrospective Study. Oncology Sawa, A., Bando, H., Kamohara, R., Takeuchi, N., Terasaki, A., Okazaki, M., Iguchi-Manaka, A., Hara, H. 2022; 100 (11): 591-601

  Abstract

  Recently, absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) have been reported to be prognostic and/or predictive factors in breast cancer. However, most of the investigations on the relationship between systemic inflammatory markers and prognosis have been conducted perioperatively, with few studies reporting on patients with metastatic or recurrent breast cancer (MBC). Here, we investigated the role of ALC and NLR as prognostic factors of MBC.This was a retrospective observational study of patients with MBC treated at the University of Tsukuba Hospital between 2013 and 2020. ALC and NLR clinical data were obtained from the patients' charts. Based on the previous reports, the cutoff value of ALC was set at 1,500/µL and that of NLR, at 3. We investigated the prognostic significance of ALC and NLR.About 80% of the 243 included patients were hormone receptor-positive, 20% were HER2-positive, and 10% were triple negative. The patients were grouped as follows: 114 (46.9%) and 129 (53.1%) in the high and low ALC groups and 145 (59.7%) and 98 (40.3%) in the high and low NLR groups, respectively. The group with high ALC at diagnosis of MBC showed significantly better prognosis (p = 0.002), and the median overall survival (OS) was 70.9 months, as compared with 40.2 months for the low ALC group. On multivariate analysis, visceral metastasis, subtype, and ALC were independent variables for OS; the NLR status was not correlated with OS.Analysis of real-world data suggests that ALC at diagnosis of MBC is an independent prognostic factor.

  View details for DOI 10.1159/000526963

  View details for PubMedID 36099888

• Long-Term Fluorescent Tissue Marking Using Tissue-Adhesive Porphyrin with Polycations Consisting of Quaternary Ammonium Salt Groups. International journal of molecular sciences Komatsu, Y., Yoshitomi, T., Furuya, K., Ikeda, T., Terasaki, A., Hoshi, A., Kawazoe, N., Chen, G., Matsui, H. 2022; 23 (8)

  Abstract

  Localization of tumors during laparoscopic surgery is generally performed by locally injecting India ink into the submucosal layer of the gastrointestinal tract using endoscopy. However, the location of the tumor is obscured because of the black-stained surgical field and the blurring caused by India ink. To solve this problem, in this study, we developed a tissue-adhesive porphyrin with polycations consisting of quaternary ammonium salt groups. To evaluate the ability of tissue-adhesive porphyrin in vivo, low-molecular-weight hematoporphyrin and tissue-adhesive porphyrin were injected into the anterior wall of the exposed stomach in rats. Local injection of low-molecular-weight hematoporphyrin into the anterior wall of the stomach was not visible even after 1 day because of its rapid diffusion. In contrast, the red fluorescence of the tissue-adhesive porphyrin was visible even after 7 days due to the electrostatic interactions between the positively-charged moieties of the polycation in the tissue-adhesive porphyrin and the negatively-charged molecules in the tissue. In addition, intraperitoneal injection of tissue-adhesive porphyrin in rats did not cause adverse effects such as weight loss, hepatic or renal dysfunction, or organ adhesion in the abdominal cavity. These results indicate that tissue-adhesive porphyrin is a promising fluorescent tissue-marking agent.

  View details for DOI 10.3390/ijms23084218

  View details for PubMedID 35457034

  View details for PubMedCentralID PMC9029083

• Elevated Production of Mitochondrial Reactive Oxygen Species via Hyperthermia Enhanced Cytotoxic Effect of Doxorubicin in Human Breast Cancer Cell Lines MDA-MB-453 and MCF-7. International journal of molecular sciences Terasaki, A., Kurokawa, H., Ito, H., Komatsu, Y., Matano, D., Terasaki, M., Bando, H., Hara, H., Matsui, H. 2020; 21 (24)

  Abstract

  Hyperthermia (HT) treatment is a noninvasive cancer therapy, often used with radiation therapy and chemotherapy. Compared with 37 °C, 42 °C is mild heat stress for cells and produces reactive oxygen species (ROS) from mitochondria. To involve subsequent intracellular accumulation of DOX, we have previously reported that the expression of ATP-binding cassette sub-family G member 2 (ABCG2), an exporter of doxorubicin (DOX), was suppressed by a larger amount of intracellular mitochondrial ROS. We then hypothesized that the additive effect of HT and chemotherapy would be induced by the downregulation of ABCG2 expression via intracellular ROS increase. We used human breast cancer cell lines, MCF-7 and MDA-MB-453, incubated at 37 °C or 42 °C for 1 h to clarify this hypothesis. Intracellular ROS production after HT was detected via electron spin resonance (ESR), and DOX cytotoxicity was calculated. Additionally, ABCG2 expression in whole cells was analyzed using Western blotting. We confirmed that the ESR signal peak with HT became higher than that without HT, indicating that the intracellular ROS level was increased by HT. ABCG2 expression was downregulated by HT, and cells were injured after DOX treatment. DOX cytotoxicity enhancement with HT was considered a result of ABCG2 expression downregulation via the increase of ROS production. HT increased intracellular ROS production and downregulated ABCG2 protein expression, leading to cell damage enhancement via DOX.

  View details for DOI 10.3390/ijms21249522

  View details for PubMedID 33333736

  View details for PubMedCentralID PMC7765207

• Enhancement of PDT-cytotoxicity <i>via</i> ROS induced by indomethacin in metastatic breast cancer JOURNAL OF PORPHYRINS AND PHTHALOCYANINES Terasaki, A., Kurokawa, H., Indo, H. P., Bando, H., Hara, H., Majima, H. J., Matsui, H., Ito, H. 2019; 23 (11-12): 1440-1447

  View details for DOI 10.1142/S1088424619501542

  View details for Web of Science ID 000508130500023

• Exacerbation of prothrombin time-international normalized ratio before second polymyxin B cartridge hemoperfusion predicts poor outcome of patients with severe sepsis and/or septic shock. The Journal of surgical research Ishizuka, M., Terasaki, A., Kubota, K. 2016; 200 (1): 308-14

  Abstract

  Although polymyxin B cartridge hemoperfusion (PMX) has an important place in the treatment of patients with severe sepsis and/or septic shock (SS), there are few rigid indications for performing PMX a second time.The objective of the study was to investigate the clinicolaboratory characteristics (CCs) showing the most significant change from the first to the second PMX and associated with 28-d mortality in patients with SS.Between April 2006 and March 2008, 78 patients with SS who had received two sessions of PMX in a prospectively collected multicenter collaboration study were enrolled. Univariate and multivariate analyses using the differences in the values of individual CCs (Δ-CCs) were performed to assess the CCs showing the most significant change in value associated with 28-d mortality. The Δ-CC was defined as: Δ2nd-1st-CC = value of the CC just before the second PMX - value of the CC just before the first PMX.Among 28 Δ2nd-1st-CCs, 10 Δ2nd-1st-CCs were selected by using receiver operating characteristic (ROC) curve analyses. The results of multivariate analysis using adequate 8 Δ2nd-1st-CCs that had been selected by univariate analyses revealed that only Δ2nd-1st-prothrombin time-international normalized ratio (PT-INR) (≤0.16/>0.16; hazard ratio = 6.562; 95% CI = 1.525-28.23; P = 0.012) was associated with 28-d mortality. Survival curve analysis demonstrated a significant difference in 28-d mortality between patients with a lower (≤0.16) and a higher (>0.16) Δ2nd-1st-PT-INR (P < 0.001).Patients with exacerbation of PT-INR (>0.16) after initial PMX are unlikely to benefit clinically from a second PMX for treatment of SS.

  View details for DOI 10.1016/j.jss.2015.07.041

  View details for PubMedID 26319975