University of the Ryukyus · Faculty of Medicine

Research keywords口腔癌・EphA4・メトロノーム化学療法・腫瘍血管形成・がん幹細胞

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• Higher overall survival rates of oral squamous cell carcinoma treated with metronomic neoadjuvant chemotherapy2024 · Shinichiro Kina, Sho Miyamoto, Reika Kawabata-Iwakawa, Mika Kina-Tanada, Masaru Ogawa, Satoshi Yokoo
• Trypanosoma cruzi assembles host cytoplasmic processing bodies to evade the innate immune response2024 · Eri Seto, Shinichiro Kina, Reika Kawabata-Iwakawa, Makiko Suzuki, Yoko Onizuka, Junko Nakajima-Shimada
• EphA4 signaling is involved in the phenotype of well-differentiated oral squamous cell arcinoma with decreased tumor immunity2023 · Metronomic chemotherapy is defined as a high-frequency low-dose schedule of chemotherapy drug administration. Although metronomic chemotherapy is widely used, the mechanisms underlying resistance to metronomic chemotherapy remain unclear. Therefore, we herein conducted a single institutional phase I/II trial to assess the efficacy and safety of metronomic chemotherapy with bleomycin plus S-1, an oral 5-FU prodrug, in the neoadjuvant setting for patients with oral squamous cell carcinoma (OSCC). The response rate of well-differentiated OSCC to metronomic chemotherapy was significantly lower. We investigated differences in molecular profiles between poorly or moderately differentiated head and neck squamous cell carcinoma (HNSCC) and well-differentiated HNSCC from patients with HNSCC TCGA data. EphA4 expression positively correlated with histological differentiation. An upstream regulator analysis correlated with EphA4 expression identified pathways associated with decreased mTORC1 signaling and T cell activation, including TCR, CD3, CD28, and CD40LG. An EphA4 blocking peptide (KYL) induced mTOR activation in well-differentiated OSCC cell lines. Plasmacytoid dendritic cell and CD8+ T cell numbers were higher in the microenvironment of poorly or moderately differentiated HNSCC than in that of well-differentiated HNSCC. Well-differentiated HNSCC had the characteristics of "cold tumors" (immune-excluded tumors). Moreover, KYL used with chemotherapeutic drugs synergistically increased cancer cell death. Well-differentiated OSCC is depleted of immune cells, which may be partly explained by the receptor tyrosine kinase EphA4.
• Exploring olfactory receptor family 7 subfamily C member 1 as a novel oral cancer stem cell target for immunotherapy2023 · The mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that share characteristics associated with normal stem cells, including self-renewal and multi-differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen-specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC-2 and HSC-3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G-protein-coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell-targeted immunotherapy, in CSC-targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen-A24-restricted OR7C1 oral CSC-specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC-targeted immunotherapy in oral cancer.

• Wnt 経路を介した組織学的分化度依存的に生じる腫瘍血管形成機構の解明2024 · 基盤研究(C)
• EphA4活性化により生じる高分化型口腔癌メトロノーム化学療法耐性機構の解明2021 · S-1は、口腔扁平上皮癌において使用頻度の高い経口抗がん剤である。申請者は、術前にbleomycin およびS-1 を低容量頻回投与（メトロノーム）化学療法が行われた舌扁平上皮癌患者の抗がん剤感受性を後ろ向きに解析した。その結果、高分化型腫瘍の方が、腫瘍が完全に消失する pathological complete response (pCR) の割合が低くなっていることが判明した。TCGA のデータを用いた結果、受容体型チロシンキナーゼEphA4 が高分化型腫瘍で高発現していることがわかった。高分化型由来の口腔がん細胞株においても、EphA4 は高発現していた。EphA4 ブロッキングペプチドであるKYL を使用すると、口腔がん細胞株の抗がん剤による細胞死が相乗的に増大していることも判明した。また、オンラインプログラムである、Timer を使用した結果、EphA4 高発現腫瘍では、CD8 陽性ナイーブおよびメモリーT細胞、さらに、形質細胞様樹状細胞の浸潤が抑制されていることもわかった。線形回帰分析を行った結果、EphA4の発現は、TNF-α, IL-6, IL-8, およびCXCL-3 の発現と負の相関があること、さらに、KYL 処理によりこれらのサイトカインが高分化型口腔癌細胞株において発現上昇することを確認した。これらの知見より、高分化型扁平上皮癌が有するメトロノーム化学療法耐性機構には、EphA4 が関わっていることが示唆された。現在までに、メトロノーム化学療法耐性には、腫瘍免疫系の不活性化が関与していることが明らかになっている。
• 抗癌剤耐性高分化型口腔癌に対するEphA4を標的とした分子生学的メカニズムの解明2018 · ■■■
• 抗癌剤曝露依存的に活性化されるEphA4 を標的とした新規治療戦略の構築2017 · 基盤研究(C)

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