博士(医学), 北海道大学, 2025年03月

小細胞肺癌

がん分子標的治療

K-ras

肺癌

ライフサイエンス, 腫瘍生物学

ライフサイエンス, 腫瘍診断、治療学

Neutrophil-Macrophage Interactions Shape Inflammatory Macrophage Remodeling in Gastric Cancer During Chemo-Immunotherapy.
Keita H Nagaoka; Hiroki Yamashita; Chiaki Mashima; Guoqiang Zhang; Hitoshi Saito; Tatsunori Minamide; Takuya Nakatsuru; Ryo Kamata; Shunsuke A Sakai; Gaku Yamamoto; Tomoko Y Morita; Kazuki Nakai; Yumi Hakozaki; Kumi Kinoshita; Yui Takahashi; Izuma Nakayama; Akihito Kawazoe; Sai M Pulukuri; Yuko Ishii; Hiroshi Haeno; Yukie Kashima; Kohei Shitara; Tomonori Yano; Takeshi Saito; Akihiro Ohashi
Cancer science, 2026年05月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The tumor microenvironment (TME) in gastric cancer (GC) is a dynamic ecosystem where immune, stromal, and malignant cells influence therapeutic outcomes. Although macrophages and neutrophils are key regulators of the TME, their coordinated responses to distinct treatments remain unclear. In this study, we performed single-cell RNA sequencing on GC biopsy specimens from treatment-naïve (TN) patients, as well as patients treated with chemotherapy (C), chemotherapy plus nivolumab (CN), or chemotherapy plus trastuzumab (CT). Comparative analyses revealed marked remodeling of the myeloid compartment, particularly involving the CN group. Neutrophils in the CN group exhibited transcriptional reprogramming, characterized by major histocompatibility complex (MHC) class II expression, inflammatory activation, and enrichment of maturation-related signatures. Pseudotime and ligand-receptor analyses identified neutrophils as a prominent sender of signals communicating with macrophages via chemokine and cytokine signaling. These neutrophil-derived signals promoted macrophage polarization toward a CXCL10+ M1-like phenotype and activated inflammatory signaling pathways. In vivo validation using a syngeneic CT26 mouse model confirmed that neutrophil depletion abolished the antitumor efficacy of combined oxaliplatin and PD-1 blockade, underscoring the functional importance of this crosstalk. Collectively, our findings demonstrate that PD-1 blockade combined with chemotherapy reprograms the GC TME by enhancing neutrophil-macrophage interactions, which amplify inflammatory signaling and strengthen antitumor immunity. These results highlight the myeloid-centered axis as a potential determinant of immunotherapy responses in GC.

A cDC1-NK/T-Malignant Cell Circuit Drives Immunogenic Remodeling Under PD-1 Blockade in Gastric Cancer.
Takuya Nakatsuru; Hiroki Yamashita; Chiaki Mashima; Guoqiang Zhang; Hitoshi Saito; Tatsunori Minamide; Keita H Nagaoka; Ryo Kamata; Shunsuke A Sakai; Gaku Yamamoto; Tomoko Y Morita; Kazuki Nakai; Yumi Hakozaki; Kumi Kinoshita; Yui Takahashi; Izuma Nakayama; Akihito Kawazoe; Yuko Ishii; Sai M Pulukuri; Hiroshi Haeno; Yukie Kashima; Kohei Shitara; Tomonori Yano; Takeshi Saito; Akihiro Ohashi
Cancer science, 2026年05月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The gastric cancer (GC) tumor microenvironment (TME) constitutes a complex and dynamic ecosystem in which immune, stromal, and malignant cells (MCs) collectively shape therapeutic responses. The dynamics of GC TME remodeling in different treatment contexts remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of GC biopsy specimens from treatment-naïve patients (TN) and patients treated with chemotherapy (C), chemotherapy plus nivolumab (CN), or chemotherapy plus trastuzumab (CT), and found that CN treatment enhanced natural killer (NK)/T cell-associated immunogenicity in GC TMEs. In CN TMEs, MCs upregulate MHC-I- and inflammation-related genes. Conventional type 1 dendritic cells (cDC1), one subcluster of dendritic cells (DCs), concurrently exhibited activation of antigen-presentation and T cell-stimulatory programs, indicating intensified communication between NK/CD8+ T cells and cDC1 in the CN TMEs. The cell-cell interaction analyses uncovered an intensified X-C Motif Chemokine Ligand 1 (XCL1) - X-C motif chemokine receptor 1 (XCR1) chemotactic axis linking NK/CD8+ T cells and cDC1, highlighting the formation of "the MCs-cDC1-NK/CD8+ T cells circuit" to reinforce antitumor immunity in the CN TMEs. Furthermore, a reduced cytotoxic NK sub-cluster, which showed high XCL1 expression, was enriched among CN responders, and its transcriptional signature was significantly correlated with favorable survival in the Cancer Genome Atlas GC cohort. Our findings delineate an immunostimulatory circuit driven by NK/CD8+ T-DCs-MCs interactions to orchestrate the immune cycle under CN therapy in GC TMEs.

PARP inhibitors elicit a cellular senescence mediated inflammatory response in homologous recombination proficient cancer cells.
Misato Kamii; Ryo Kamata; Hitoshi Saito; Gaku Yamamoto; Chiaki Mashima; Toyohiro Yamauchi; Takehiro Nakao; Yuta Sakae; Tomoko Yamamori-Morita; Kazuki Nakai; Yumi Hakozaki; Masataka Takenaka; Aikou Okamoto; Akihiro Ohashi
Scientific reports, 15, 1, 15458, 15458, 2025年05月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Poly (ADP-ribose) polymerase (PARP) inhibitors have improved the prognosis of homologous recombination deficient (HRD) ovarian cancer (OC), while effective therapeutic strategies for HR-proficient (HRP) OC still need to be established. This study investigates senescence-mediated inflammation as a novel mechanism of action for PARP inhibitors in HRP cancers. Transcriptome analyses were performed in olaparib-treated HeLa cells as a HRP model. Interferon regulatory factor-Lucia luciferase (IRF-Luc) reporter activity was assessed. The effects of PARP inhibitors on senescence-like phenotypes were assessed in seven HRP cancer cell lines, based on morphological changes, senescence-associated β-galactosidase (SA-β-GAL) activity, cellular granularity, and senescence-associated secretory phenotype (SASP)-related gene expression. Peripheral blood mononuclear cell (PBMC) migration assays were also performed with the conditioned medium in treatment with the PARP inhibitor. Transcriptome analyses revealed numbers of inflammatory cytokine- and chemokine-related pathways were significantly upregulated in olaparib-treated HeLa cells, which were confirmed by IRF-Luc reporter assays. The PARP inhibitors induced senescent phenotypes in HRP cancer cell lines: flattened and enlarged morphology, increased SA-β-GAL activity, elevated cellular granularity, and upregulated expressions of SASP-related genes (e.g., IL1B, IL6, and CXCL10). Furthermore, in vitro migration assays revealed that PARP inhibitor-treated HRP cancer cells attracted PBMCs more abundantly, suggesting the potential for recruiting immune cells to HRP cancer cells through senescence-mediated immunological activation. Our findings suggest that PARP inhibitors recruit immune cells to HRP cancer cells, potentially activating immune responses in the tumor microenvironment, providing new insights into the clinical benefits of PARP inhibitors in immunotherapy for patients with HRP OC.

SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis
Akane Ogawa; Keiichi Izumikawa; Sota Tate; Sho Isoyama; Masaru Mori; Kohei Fujiwara; Soyoka Watanabe; Takayuki Ohga; Ukhyun Jo; Daiki Taniyama; Shojiro Kitajima; Soichiro Tanaka; Hiroshi Onji; Shun-Ichiro Kageyama; Gaku Yamamoto; Hitoshi Saito; Tomoko Yamamori Morita; Masayasu Okada; Manabu Natsumeda; Masami Nagahama; Junya Kobayashi; Akihiro Ohashi; Hiroyuki Sasanuma; Shigeki Higashiyama; Shingo Dan; Yves Pommier; Junko Murai
Molecular Cell, 85, 5, 894, 912.e10, Elsevier BV, 2025年03月, ［査読有り］
研究論文（学術雑誌）

WEE1 confers resistance to KRASG12C inhibitors in non-small cell lung cancer
Gaku Yamamoto; Kosuke Tanaka; Ryo Kamata; Hitoshi Saito; Tomoko Yamamori-Morita; Takehiro Nakao; Jie Liu; Shunta Mori; Shigehiro Yagishita; Akinobu Hamada; Yuki Shinno; Tatsuya Yoshida; Hidehito Horinouchi; Yuichiro Ohe; Shun-Ichi Watanabe; Yasushi Yatabe; Hidenori Kitai; Satoshi Konno; Susumu S. Kobayashi; Akihiro Ohashi
Cancer Letters, 611, 217414, 217414, Elsevier BV, 2025年02月, ［査読有り］, ［筆頭著者］
研究論文（学術雑誌）

Risk and survival of patients with non-small cell lung cancer and pre-existing autoimmune disorders receiving immune checkpoint blockade therapy: Survival analysis with inverse probability weighting from a nationwide, multi-institutional, retrospective study (NEJ047)
Tetsuhiko Asao; Takehito Shukuya; Kohei Uemura; Rui Kitadai; Gaku Yamamoto; Atsuto Mouri; Meiyo Tamaoka; Ryosuke Imai; Yoko Tsukita; Kazutoshi Isobe; Satoshi Watanabe; Mitsuhiro Kamimura; Ryo Morita; Keita Kudo; Minehiko Inomata; Kazunari Tateishi; Kazutaka Kakinuma; Hiroshige Yoshioka; Yukiko Namba; Issei Sumiyoshi; Taku Nakagawa; Kana Watanabe; Kunihiko Kobayashi; Kazuhisa Takahashi
Lung Cancer, 194, 107894, 107894, Elsevier BV, 2024年08月, ［査読有り］
研究論文（学術雑誌）

An algorithm-based technique for counting mitochondria in cells using immunohistochemical staining of formalin-fixed and paraffin-embedded sections
Mai Sakashita; Noriko Motoi; Gaku Yamamoto; Emi Gambe; Masanori Suzuki; Yukihiro Yoshida; Shun-ichi Watanabe; Yutaka Takazawa; Kazunori Aoki; Atsushi Ochiai; Shingo Sakashita
Journal of Cancer Research and Clinical Oncology, 150, 4, Springer Science and Business Media LLC, 2024年04月03日, ［査読有り］
研究論文（学術雑誌）, Abstract

Purpose

Visualizing mitochondria in cancer cells from human pathological specimens may improve our understanding of cancer biology. However, using immunohistochemistry to evaluate mitochondria remains difficult because almost all cells contain mitochondria and the number of mitochondria per cell may have important effects on mitochondrial function. Herein, we established an objective system (Mito-score) for evaluating mitochondria using machine-based processing of hue, saturation, and value color spaces.

Methods

The Mito-score was defined as the number of COX4 (mitochondrial inner membrane) immunohistochemistry-positive pixels divided by the number of nuclei per cell. The system was validated using four lung cancer cell lines, normal tissues, and lung cancer tissues (199 cases).

Results

The Mito-score correlated with MitoTracker, a fluorescent dye used to selectively label and visualize mitochondria within cells under a microscope (R² = 0.68) and with the number of mitochondria counted using electron microscopy (R² = 0.79). Histologically, the Mito-score of small cell carcinoma (57.25) was significantly lower than that of adenocarcinoma (147.5, p < 0.0001), squamous cell carcinoma (120.6, p = 0.0004), and large cell neuroendocrine carcinoma (111.8, p = 0.002).

Conclusion

The Mito-score method enables the analysis of the mitochondrial status of human formalin-fixed paraffin-embedded specimens and may provide insights into the metabolic status of cancer.

CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
Tomoko Yamamori Morita; Jie Yu; Yukie Kashima; Ryo Kamata; Gaku Yamamoto; Tatsunori Minamide; Chiaki Mashima; Miyuki Yoshiya; Yuta Sakae; Toyohiro Yamauchi; Yumi Hakozaki; Shun-ichiro Kageyama; Akito Nakamura; Eric Lightcap; Kosuke Tanaka; Huifeng Niu; Karuppiah Kannan; Akihiro Ohashi
Nature Communications, 14, 1, Springer Science and Business Media LLC, 2023年11月18日, ［査読有り］
研究論文（学術雑誌）, Abstract

Serine/threonine kinase, cell division cycle 7 (CDC7) is critical for initiating DNA replication. TAK-931 is a specific CDC7 inhibitor, which is a next-generation replication stress (RS) inducer. This study preclinically investigates TAK-931 antitumor efficacy and immunity regulation. TAK-931 induce RS, generating senescence-like aneuploid cells, which highly expressed inflammatory cytokines and chemokines (senescence-associated secretory phenotype, SASP). In vivo multilayer-omics analyses in gene expression panel, immune panel, immunohistochemistry, RNA sequencing, and single-cell RNA sequencing reveal that the RS-mediated aneuploid cells generated by TAK-931 intensively activate inflammatory-related and senescence-associated pathways, resulting in accumulation of tumor-infiltrating immune cells and potent antitumor immunity and efficacy. Finally, the combination of TAK-931 and immune checkpoint inhibitors profoundly enhance antiproliferative activities. These findings suggest that TAK-931 has therapeutic antitumor properties and improved clinical benefits in combination with conventional immunotherapy.

Use of bronchoalveolar lavage in diagnosing angioimmunoblastic T‐cell lymphoma: A case report
Gaku Yamamoto; Kei Takamura; Yuriko Ishida; Yuma Sato; Ayuka Sinozaki; Hajime Kikuchi; Makoto Yamamoto; Hajime Kobayashi; Naoki Hirose; Keisuke Kikuchi
Respirology Case Reports, 10, 4, Wiley, 2022年03月03日, ［査読有り］, ［筆頭著者］
研究論文（学術雑誌）, Abstract

Angioimmunoblastic T‐cell lymphoma (AITL) is a type of peripheral T‐cell tumour that belongs to the group of non‐Hodgkin's lymphomas. Pulmonary lesions can be found in 7%–10% of AITL cases. Imaging findings of the lungs varied; however, immunoblastic infiltration in the lungs is rare. Our patient was a 73‐year‐old man who received repeated chemotherapy for AITL. Fourth‐line therapy using romidepsin controlled the illness, but the patient was hospitalized for dyspnoea and an infiltrative shadow. We performed bronchoalveolar lavage (BAL), and the culture was positive for Haemophilus influenzae. The patient was initially discharged with antibiotic therapy, but hospitalized again. Antibiotics were ineffective and the patient required mechanical ventilation. BAL was performed again, after which fluid cytology revealed immunoblast‐like atypical cells. Therefore, the patient was diagnosed with pulmonary infiltration due to AITL. Steroid therapy proved ineffective, and the patient died. BAL was used to effectively diagnose pulmonary AITL infiltration.

First-line osimertinib in elderly patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer: a retrospective multicenter study (HOT2002)
Gaku Yamamoto; Hajime Asahina; Osamu Honjo; Toshiyuki Sumi; Atsushi Nakamura; Kenichiro Ito; Hajime Kikuchi; Fumihiro Hommura; Ryoichi Honda; Keiki Yokoo; Yuka Fujita; Satoshi Oizumi; Ryo Morita; Yasuyuki Ikezawa; Hisashi Tanaka; Nozomu Kimura; Takaaki Sasaki; Noriaki Sukoh; Taichi Takashina; Toshiyuki Harada; Hirotoshi Dosaka-Akita; Hiroshi Isobe; Gaku Yamamoto; Hajime Asahina; Osamu Honjo; Toshiyuki Sumi; Atsushi Nakamura; Kenichiro Ito; Hiroshi Isobe; Hajime Kikuchi; Fumihiro Hommura; Ryoichi Honda; Keiki Yokoo; Yuka Fujita; Satoshi Oizumi; Ryo Morita; Yasuyuki Ikezawa; Hisashi Tanaka; Nozomu Kimura; Takaaki Sasaki; Noriaki Sukoh; Taichi Takashina; Toshiyuki Harada; Hirotoshi Akita
Scientific Reports, 11, 1, Springer Science and Business Media LLC, 2021年11月30日, ［査読有り］, ［筆頭著者］
研究論文（学術雑誌）, Abstract

Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1–73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9–23.9) months. The median overall survival was not reached (95% confidence interval 24.6–not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

高齢者の未治療EGFR遺伝子変異陽性非小細胞肺癌に対するオシメルチニブの有効性・安全性に関する後ろ向き検討
山本 岳; 朝比奈 肇; 伊藤 祥太郎; 古田 恵; 水柿 秀紀; 菊地 順子; 菊地 英毅; 榊原 純; 品川 尚文; 今野 哲
肺癌, 61, 1, 66, 66, (NPO)日本肺癌学会, 2021年02月
日本語

気管支鏡ナビゲーションにおけるAIの活用
國崎 守; 品川 尚文; 山本 岳; 辻 康介; 伊藤 祥太郎; 佐藤 峰嘉; 高橋 宏典; 高島 雄太; 古田 恵; 庄司 哲明; 朝比奈 肇; 菊地 英毅; 菊地 順子; 榊原 純; 今野 哲
気管支学, 42, 6, 575, 576, (NPO)日本呼吸器内視鏡学会, 2020年11月
日本語

高齢者未治療EGFR遺伝子変異陽性非小細胞肺癌に対するオシメルチニブの有効性・安全性に関する後ろ向き検討
山本 岳; 朝比奈 肇; 伊藤 祥太郎; 古田 恵; 水柿 秀紀; 菊地 順子; 菊地 英毅; 榊原 純; 品川 尚文; 今野 哲
肺癌, 60, 6, 564, 564, (NPO)日本肺癌学会, 2020年10月
日本語

Pulmonary capillary hemangiomatosis-predominant vasculopathy in a patient with rheumatoid arthritis-associated interstitial lung disease: An autopsy report
Junichi Nakamura; Ichizo Tsujino; Gaku Yamamoto; Toshitaka Nakaya; Kei Takahashi; Hirokazu Kimura; Takahiro Sato; Taku Watanabe; Shimpei Nakagawa; Noriyuki Otsuka; Hiroshi Ohira; Satoshi Konno
Respiratory Medicine Case Reports, 31, 101215, 101215, Elsevier BV, 2020年, ［査読有り］
研究論文（学術雑誌）

Response to First-Line Osimertinib Treatment in Non–Small-Cell Lung Cancer With Coexisting G719A and Primary T790M Epidermal Growth Factor Receptor Mutations
Tomoo Ikari; Jun Sakakibara-Konishi; Gaku Yamamoto; Hidenori Kitai; Hidenori Mizugaki; Hajime Asahina; Eiki Kikuchi; Naofumi Shinagawa
Clinical Lung Cancer, 20, 4, e531, e533, Elsevier BV, 2019年07月, ［査読有り］
研究論文（学術雑誌）

Response of BRAFV600E-Mutant Lung Adenocarcinoma With Brain Metastasis and Leptomeningeal Dissemination to Dabrafenib Plus Trametinib Treatment
Gaku Yamamoto; Jun Sakakibara-Konishi; Tomoo Ikari; Hidenori Kitai; Hidenori Mizugaki; Hajime Asahina; Eiki Kikuchi; Naofumi Shinagawa
Journal of Thoracic Oncology, 14, 5, e97, e99, Elsevier BV, 2019年05月, ［査読有り］, ［筆頭著者］
研究論文（学術雑誌）

肺癌診療ガイドライン2024年版update-薬物治療を中心に IV期非小細胞肺癌ドライバー遺伝子変異/転座陽性 5)RET陽性肺癌治療の展望
山本岳; 葉清隆, 月刊呼吸器内科, 48, 1, 2025年

肺がん薬物療法副作用マネジメント = Professional management techniques for adverse events in systemic therapy for lung cancer
倉田, 宝保; 吉岡, 弘鎮; 金田, 俊彦, Crizotinib
メジカルビュー社, 2025年11月, 9784758322492, 463p, 日本語, ［分担執筆］

臨床検体を用いたGenexus/Oncomine Precision Assay（OPA）の性能評価
山本 岳; 泉 大樹; 松本 慎吾; 宇田川 響; 西野 和美; 村上 修司; 杉坂 淳; 仲地 一郎; 榊原 純; 後藤 功一
第66回日本肺癌学会学術集会, 日本語, 口頭発表（一般）
2025年11月06日 - 2025年11月08日

Targeting WEE1 to improve the therapy of KRAS G12C mutant non-small cell lung cancer.
Yamamoto G, Tanaka K, Kamata R, Mori S, Liu J, Yamauchi T, Sakae Y, Ohashi A. Kobayashi SS.
AACR Annual meeting 2023

WEE1 inhibition prevents and overcomes resistance to KRAS inhibitors in lung cancer by enhancing MCL1-mediated apoptosis.
Yamamoto G.; Tanaka K.; Kamata R.; Takehiro N.; Mori S.; Liu J.; Kobayashi SS; Ohashi A.
AACR Annual meeting 2024

KRAS変異肺癌の治療抵抗性メカニズムの解明
科学研究費助成事業
2026年04月01日 - 2029年03月31日
山本 岳
日本学術振興会, 若手研究, 国立研究開発法人国立がん研究センター, 26K18754

KRAS変異肺がんの治療抵抗性克服を目指した新規分子標的併用療法の開発
科学研究費助成事業
2024年04月23日 - 2026年03月31日
山本 岳
日本学術振興会, 特別研究員奨励費, 北海道大学, 24KJ0251