東京大学
医学系研究科
外科診療部門
胸部外科
English
更新日：2022/06/30
特任教授
カキミ　　カズヒロ
垣見　　和宏
  • 1963年生まれ

所属

  1. 東京大学医学部附属病院特任教授
  2. 東京大学医学部附属病院

プロフィール

  1. 学歴<br />
    昭和63年 京都大学医学部卒業<br />
    平成7年 京都大大学大学院医学研究科 内科系修了<br />
    博士(医学)(京都大学)取得<br />
    指導教官：石本秋稔教授（京都大学ウイルス研究所）、<br />
    栗林景容教授（三重大学医学部生体防御医学講座）<br />
    腫瘍免疫学<br /><br />
    職歴<br />
    平成 7年～ 8年：三重大学医学部 助手<br />
    生体防御医学講座（栗林教授研究室）でウイルスおよび腫瘍特異的細胞性免疫応答について研究<br />
    平成 8年～13年：スクリプス研究所 客員研究員<br />
    平成13年～14年：同上 客員助教授<br />
    Francis V. Chisari博士研究室で細胞性免疫応答に関する研究に従事<br />
    平成14年～16年：東京医科大学医学部 消化器内科 助手（森安史典教授） 肝がんに対する細胞性免疫応答および免疫治療法の開発について研究<br />
    平成16年～26年：東京大学医学部附属病院 免疫細胞治療学講座 特任准教授<br />
    平成26年～現在：同上 特任教授<br />
    東京大学にて腫瘍免疫学の研究と、がん免疫治療の臨床研究に従事

学位

  1. 医学博士京都大学

研究分野

  1. ライフサイエンス免疫学

研究キーワード

  1. 免疫細胞治療
  2. 癌免疫
  3. immuntoherapy
  4. cancer immunology

論文

  1. Principal component analysis of early immune cell dynamics during pembrolizumab treatment of advanced urothelial carcinoma.2022/08Taro Teshima Yukari Kobayashi Taketo Kawai Yoshihiro Kushihara Koji Nagaoka Jimpei Miyakawa Yoshiyuki Akiyama Yuta Yamada Yusuke Sato Daisuke Yamada Nobuyuki Tanaka Tatsuhiko Tsunoda Haruki Kume Kazuhiro KakimiOncology letters24/ 2, 265-265研究論文（学術雑誌）10.3892/ol.2022.13384Immune checkpoint inhibitors have been approved as second-line therapy for patients with advanced urothelial carcinoma (UC). However, which patients will obtain clinical benefit remains to be determined. To identify predictive biomarkers for the pembrolizumab (PEM) response early during treatment, the present study investigated 31 patients with chemotherapy-resistant recurrent or metastatic UC who received 200 mg PEM intravenously every 3 weeks. Blood was taken just before the first dose and again before the second dose, and the peripheral blood mononuclear cells of all 31 pairs of blood samples were immune phenotyped by flow cytometry. Data were assessed by principal component analysis (PCA), correlation analysis and Cox proportional hazards modeling in order to comprehensively determine the effects of PEM on peripheral mononuclear immune cells. Absolute counts of CD45RA+CD27-CCR7- terminally differentiated CD8+ T cells and KLRG1+CD57+ senescent CD8+ T cells were significantly increased after PEM administration (P=0.042 and P=0.043, respectively). Senescent and exhausted CD4+ and CD8+ T cell dynamics were strongly associated with each other. By contrast, counts of monocytic myeloid-derived suppressor cells (mMDSCs) were not associated with other immune cell phenotypes. The results of PCA and non-hierarchical clustering of patients suggested that excessive T cell senescence and differentiation early during treatment were not necessarily associated with a survival benefit. However, decreased mMDSC counts after PEM were associated with improved overall survival. In conclusion, early on-treatment peripheral T cell status was associated with response to PEM; however, it was not associated with clinical benefit. By contrast, decreased peripheral mMDSC counts did predict improved overall survival.
  2. Selection of RNA-based evaluation methods for tumor microenvironment by comparing with histochemical and flow cytometric analyses in gastric cancer.2022/05/20Noriyuki Saito Yasuyoshi Sato Hiroyuki Abe Ikuo Wada Yukari Kobayashi Koji Nagaoka Yoshihiro Kushihara Tetsuo Ushiku Yasuyuki Seto Kazuhiro KakimiScientific reports12/ 1, 8576-8576研究論文（学術雑誌）10.1038/s41598-022-12610-wUnderstanding the tumor microenvironment (TME) and anti-tumor immune responses in gastric cancer are required for precision immune-oncology. Taking advantage of next-generation sequencing technology, the feasibility and reliability of transcriptome-based TME analysis were investigated. TME of 30 surgically resected gastric cancer tissues was analyzed by RNA-Seq, immunohistochemistry (IHC) and flow cytometry (FCM). RNA-Seq of bulk gastric cancer tissues was computationally analyzed to evaluate TME. Computationally analyzed immune cell composition was validated by comparison with cell densities established by IHC and FCM from the same tumor tissue. Immune cell infiltration and cellular function were also validated with IHC and FCM. Cell proliferation and cell death in the tumor as assessed by RNA-Seq and IHC were compared. Computational tools and gene set analysis for quantifying CD8+ T cells, regulatory T cells and B cells, T cell infiltration and functional status, and cell proliferation and cell death status yielded an excellent correlation with IHC and FCM data. Using these validated transcriptome-based analyses, the immunological status of gastric cancer could be classified into immune-rich and immune-poor subtypes. Transcriptome-based TME analysis is feasible and is valuable for further understanding the immunological status of gastric cancer.
  3. Dietary Lactobacillus-Derived Exopolysaccharide Enhances Immune-Checkpoint Blockade Therapy.2022/05/02Hirotaka Kawanabe-Matsuda Kazuyoshi Takeda Marie Nakamura Seiya Makino Takahiro Karasaki Kazuhiro Kakimi Megumi Nishimukai Tatsukuni Ohno Jumpei Omi Kuniyuki Kano Akiharu Uwamizu Hideo Yagita Ivo Gomperts Boneca Gérard Eberl Junken Aoki Mark J Smyth Ko OkumuraCancer discovery12/ 5, 1336-1355研究論文（学術雑誌）10.1158/2159-8290.CD-21-0929Microbes and their byproducts have been reported to regulate host health and immune functions. Here we demonstrated that microbial exopolysaccharide produced by Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 (EPS-R1) induced CCR6+ CD8+ T cells of mice and humans. In mice, ingestion of EPS-R1 augmented antitumor effects of anti-CTLA-4 or anti-PD-1 monoclonal antibody against CCL20-expressing tumors, in which infiltrating CCR6+ CD8+ T cells were increased and produced IFNγ accompanied by a substantial immune response gene expression signature maintaining T-cell functions. Of note, the antitumor adjuvant effect of EPS-R1 was also observed in germ-free mice. Furthermore, the induction of CCR6 expression was mediated through the phosphorylated structure in EPS-R1 and a lysophosphatidic acid receptor on CD8+ T cells. Overall, we find that dietary EPS-R1 consumption induces CCR6+ CD8+ T cells in Peyer's patches, favoring a tumor microenvironment that augments the therapeutic effect of immune-checkpoint blockade depending on CCL20 production by tumors. SIGNIFICANCE: Gut microbiota- and probiotic-derived metabolites are attractive agents to augment the efficacy of immunotherapies. Here we demonstrated that dietary consumption of Lactobacillus-derived exopolysaccharide induced CCR6+ CD8+ T cells in Peyer's patches and improved the tumor microenvironment to augment the therapeutic effects of immune-checkpoint blockade against CCL20-producing tumors. See related commentary by Di Luccia and Colonna, p. 1189. This article is highlighted in the In This Issue feature, p. 1171.
  4. Association between effector-type regulatory T cells and immune checkpoint expression on CD8+ T cells in malignant ascites from epithelial ovarian cancer.2022/04/21Sho Sato Hirokazu Matsushita Daisuke Shintani Yukari Kobayashi Nao Fujieda Akira Yabuno Tadaaki Nishikawa Keiichi Fujiwara Kazuhiro Kakimi Kosei HasegawaBMC cancer22/ 1, 437-437研究論文（学術雑誌）10.1186/s12885-022-09534-zBACKGROUND: Regulatory T cells (Tregs) play an important role in the antitumor immune response in epithelial ovarian cancer (EOC). To understand the immune-inhibitory networks of EOC, we addressed the association between Tregs and immune checkpoint expression on T cells in the tumor microenvironment of EOC. METHODS: A total of 41 patients with stage IIIC and IV EOC were included in the analysis. We harvested cells from malignant ascites and investigated them using multi-color flow cytometry. We categorized the Tregs into 3 groups: effector-type Tregs, naïve Tregs and non-Tregs, based on the expression patterns of CD45RA and Foxp3 in CD4+ T cells. Furthermore, the relationships between the expression of various immune checkpoint molecules, such as PD-1, on CD8+ T cells and each of the Treg subtypes was also evaluated. RESULTS: The median frequency of naïve Tregs, effector-type Tregs and non-Tregs were 0.2% (0-0.8), 2.0% (0-11.4) and 1.5% (0.1-6.3) in CD4+ T cells of malignant ascites from EOC patients, respectively. A high frequency of effector-type Tregs was associated with high-grade serous carcinoma compared with the other histotypes. Patients with higher proportions of effector-type Tregs showed a trend towards increased progression-free survival. We also demonstrated a correlation between a higher proportion of effector-type Tregs and increased PD-1 expression on CD8+ T cells. In addition, C-C chemokine receptor 4 expression was also observed in effector-type Tregs. CONCLUSION: These data suggest that multiple immune-inhibitory networks exist in malignant ascites from EOC patients, suggesting an approach towards combinational immunotherapies for advanced EOC patients.
  5. Universal encoding of pan-cancer histology by deep texture representations.2022/03/01Daisuke Komura Akihiro Kawabe Keisuke Fukuta Kyohei Sano Toshikazu Umezaki Hirotomo Koda Ryohei Suzuki Ken Tominaga Mieko Ochi Hiroki Konishi Fumiya Masakado Noriyuki Saito Yasuyoshi Sato Takumi Onoyama Shu Nishida Genta Furuya Hiroto Katoh Hiroharu Yamashita Kazuhiro Kakimi Yasuyuki Seto Tetsuo Ushiku Masashi Fukayama Shumpei IshikawaCell reports38/ 9, 110424-110424研究論文（学術雑誌）10.1016/j.celrep.2022.110424Cancer histological images contain rich biological and clinical information, but quantitative representation can be problematic and has prevented the direct comparison and accumulation of large-scale datasets. Here, we show successful universal encoding of cancer histology by deep texture representations (DTRs) produced by a bilinear convolutional neural network. DTR-based, unsupervised histological profiling, which captures the morphological diversity, is applied to cancer biopsies and reveals relationships between histologic characteristics and the response to immune checkpoint inhibitors (ICIs). Content-based image retrieval based on DTRs enables the quick retrieval of histologically similar images using The Cancer Genome Atlas (TCGA) dataset. Furthermore, via comprehensive comparisons with driver and clinically actionable gene mutations, we successfully predict 309 combinations of genomic features and cancer types from hematoxylin-and-eosin-stained images. With its mounting capabilities on accessible devices, such as smartphones, universal encoding for cancer histology has a strong impact on global equalization for cancer diagnosis and therapies.
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