Tokushima University / Educator and Researcher Directory --- Morita, Yutaka

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Tokushima University ⟩ Graduate School of Biomedical Sciences ⟩ 医学域 ⟩ Endwed Collaborative Research ⟩ Contribution ⟩ 地域リウマチ・総合内科学 ⟩

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Academic Paper (Judged Full Paper):

1.	Yohei Yabuki, Atsushi Mitsuhashi, Hirokazu Ogino, Aito Yoshida, Thi Na Nguyen, Hiroto Yoneda, Ryohiko Ozaki, Yuki Tsukazaki, Yutaka Morita, Hiroshi Nokihara, Seidai Satou, Tsutomu Shinohara, Masaki Hanibuchi and Yasuhiko Nishioka : Hypoxia-inducible factor-targeting therapy augmented the sensitivity to programmed death ligand-1 blockade by enhancing interferon-γ-induced chemokines in tumor cells, International Journal of Cancer, Vol.156, No.9, 1814-1825, 2024. (Summary) Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) provide clinical benefits for various advanced malignancies. However, the predictive factors that determine sensitivity to ICIs have not been fully elucidated. We focused on tumor-derived CXCL10/11 as a pivotal factor that determines the response to PD-L1 blockade by regulating T cell accumulation and tumor angiogenesis. We previously reported that CXCL10/11 was upregulated by interferon (IFN)-γ in ICI-sensitive tumor cells but not in ICI-resistant cells, including mouse Lewis lung carcinoma (LLC). In the present study, gene silencing of tumor-derived CXCL10/11 induced resistance to PD-L1 blockade in AB1-HA mesothelioma cell-bearing mice. To identify the mechanisms underlying ICI resistance, we performed a microarray analysis to compare the IFN-γ-inducible genes between ICI-sensitive AB1-HA and ICI-resistant LLC in vitro. A pathway analysis based on microarray data indicated that hypoxia-inducible factor (HIF) 1A is the key signal that inhibits CXCL10/11 expression. We revealed that the HIF1A inhibitors echinomycin (EC) and YC-1 upregulated CXCL10/11 genes induced by IFN-γ in tumor cells in vitro. In addition, combination therapy with PD-L1 blockade and EC demonstrated synergistic antitumor effects in LLC-bearing mice. Combination therapy enhanced tumor infiltration of CD8 T cells and suppressed tumor angiogenesis. The present study suggests that HIF1A signaling in tumor cells dominates ICI resistance via the downregulation of tumor-derived CXCL10/11. (Keyword) angiogenesis / CXCL10/11 / HIF1A / immune checkpoint inhibitor / interferon-γ (Link to Publication Site) ● Publication site (DOI): 10.1002/ijc.35301 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39686841 ● Summary page in Scopus @ Elsevier: 2-s2.0-85212305972 (DOI: 10.1002/ijc.35301, PubMed: 39686841, Elsevier: Scopus)
2.	Yuki Tsukazaki, Hirokazu Ogino, Yoshio Okano, Soji Kakiuchi, Shoko Harada, Yuko Toyoda, Yugo Matsumura, Seiya Ichihara, Takeshi Imakura, Rikako Matsumoto, Ryohiko Ozaki, Ei Ogawa, Yutaka Morita, Atsushi Mitsuhashi, Yohei Yabuki, Hiroto Yoneda, Masaki Hanibuchi, Kayoko Hase, Eiji Takeuchi, Takashi Haku and Yasuhiko Nishioka : Granulocyte colony-stimulating factor has the potential to attenuate the therapeutic efficacy of chemo-immunotherapy for extensive-stage small-cell lung cancer, International Journal of Clinical Oncology, Vol.29, No.10, 1451-1460, 2024. (Summary) Granulocyte colony-stimulating factor (G-CSF) has the potential to attenuate the anti-tumor immune responses of T-cells by increasing immune suppressive neutrophils and myeloid-derived suppressor cells. However, the clinical impact of G-CSF on the efficacy of immunotherapy remains unknown. This multi-center retrospective analysis evaluated the impact of G-CSF in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with chemo-immunotherapy. We analyzed 65 patients with ES-SCLC who completed four cycles of induction chemo-immunotherapy and evaluated the effects of G-CSF on progression-free survival (PFS), overall survival (OS), and a durable response to immunotherapy (defined as PFS 12 months). Fifty patients (76.9%) received 1 dose of G-CSF. The PFS of the patients with G-CSF was poorer than that of the patients without G-CSF (median PFS 8.3 vs. 4.9 months, p = 0.009). The OS of the patients with G-CSF tended to be shorter, but not statistically significant, than that of the patients without G-CSF (median OS 24.3 vs. 16.4 months, p = 0.137). In the multivariate analysis, G-CSF administration was associated with poorer PFS (hazard ratio 2.78, 95% CI 1.36-5.69, p = 0.005) and was identified as a determinant of a durable response (odds ratio 0.18, 95% CI 0.04-0.80, p = 0.024). These results were consistent with other definitions of G-CSF administration (administration of 1 dose of pegfilgrastim, or either 5 doses of filgrastim or 1 dose of pegfilgrastim). G-CSF has the potential to attenuate the efficacy of immunotherapy; therefore, the indication for G-CSF during chemo-immunotherapy should be carefully considered for ES-SCLC. (Keyword) Chemo-immunotherapy / Extensive-stage small-cell lung cancer / Granulocyte colony-stimulating factor (Link to Publication Site) ● Publication site (DOI): 10.1007/s10147-024-02586-0 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39009900 ● Summary page in Scopus @ Elsevier: 2-s2.0-85198503607 (DOI: 10.1007/s10147-024-02586-0, PubMed: 39009900, Elsevier: Scopus)
3.	Kenya Miyamoto, Hirokazu Ogino, Takumi Kakimoto, Yugo Matsumura, Keiko Haji, Atsushi Mitsuhashi, Yutaka Morita, Yuki Tsukazaki, Yohei Yabuki, Ryohiko Ozaki, Hiroto Yoneda, Seidai Satou, Masaki Hanibuchi, Yoshimi Bando, Hiroshi Nokihara and Yasuhiko Nishioka : Transformation of epidermal growth factor receptor mutated lung adenocarcinoma to small-cell carcinoma long after the cessation of tyrosine kinase inhibitor treatment: A case series and literature review, Respiratory Medicine Case Reports, Vol.51, 102076, 2024. (Keyword) Acquired resistance / Epidermal growth factor receptor / Non-small-cell lung cancer / Small-cell lung cancer transformation / Tyrosine kinase inhibitors (Link to Publication Site) ● Publication site (DOI): 10.1016/j.rmcr.2024.102076 (Link to Search Site for Scientific Articles) ● Summary page in Scopus @ Elsevier: 2-s2.0-85196709618 (DOI: 10.1016/j.rmcr.2024.102076, Elsevier: Scopus)

Proceeding of International Conference:

1.	Yuki Tsukazaki, Hirokazu Ogino, Yoshio Okano, Soji Kakiuchi, Shoko Harada, Yuko Toyoda, Yugo Matsumura, Seiya Ichihara, Takeshi Imakura, Rikako Matsumoto, Ryohiko Ozaki, Ei Ogawa, Yutaka Morita, Atsushi Mitsuhashi, Yohei Yabuki, Hiroto Yoneda, Masaki Hanibuchi, Kayoko Hase, Eiji Takeuchi, Takashi Haku and Yasuhiko Nishioka : The Conflicting Impacts of G-CSF on the Therapeutic Efficacy of Chemoimmunotherapy for Extensive Stage Small Cell Lung Cancer, 2024 World Conference on Lung Cancer, San Diego, Sep. 2024.

Proceeding of Domestic Conference:

1.	Yuki Tsukazaki, Hirokazu Ogino, 岡野義夫, Souji Kakiuchi, Yuko Toyoda, MATSUMOTO Rikako, Ryohiko Ozaki, Yutaka Morita, Atsushi Mitsuhashi, Yohei Yabuki, Masaki Hanibuchi, 長谷加容子, 竹内栄治, 葉久貴司 and Yasuhiko Nishioka : G-CSFが進展型小細胞肺癌における化学免疫療法の治療効果に及ぼす影響を検討した多施設共同後方視的解析, 第65回日本肺癌学会学術集会, Nov. 2024.
2.	Yuki Tsukazaki, Hirokazu Ogino, 岡野義夫, Souji Kakiuchi, Yuko Toyoda, MATSUMOTO Rikako, Ryohiko Ozaki, Yutaka Morita, Atsushi Mitsuhashi, Yohei Yabuki, Masaki Hanibuchi, 長谷加容子, 竹内栄治, 葉久貴司 and Yasuhiko Nishioka : G-CSF が進展型小細胞肺癌に対する化学免疫療法の治療効果に及ぼす影響に関する解析, 第62回日本癌治療学会学術集会, Oct. 2024.
3.	Atsushi Mitsuhashi, Kazuya Koyama, Hirokazu Ogino, Yohei Yabuki, Ryohiko Ozaki, Yuki Tsukazaki, Yutaka Morita, Aito Yoshida, Hiroshi Nokihara, Masaki Hanibuchi and Yasuhiko Nishioka : Fibrocyte 制御によるがん免疫排除克服に向けた治療戦略, 第83回日本癌学会学術総会, Sep. 2024.
4.	宮本憲哉, Masaki Hanibuchi, Yuta Isomura, Yutaka Morita, 村上行人, Hiroki Bando, Ryohiko Ozaki, Kozo Kagawa, Hiroto Yoneda, Hirokazu Ogino and Yasuhiko Nishioka : 気管支鏡後の呼吸器感染症ハイリスク症例における予防的抗菌薬投与の意義についての後方視的研究, 第47回日本呼吸器内視鏡学会学術集会, Jun. 2024.