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食道扁平上皮癌における腫瘍微小環境の解析

小林, 佑哉 東京大学 DOI:10.15083/0002006940

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名 小林 佑哉
腫瘍微小環境はがん細胞と複雑な相互作用を有しており、がんの形成、生存そして転移に
大きく関わっている。がん細胞そのものではなく、微小環境をターゲットとした治療法の
開発も進んでいる。本研究は食道扁平上皮癌 97 症例に対する RNA sequencing により腫瘍
微小環境を解析したものであり、下記の結果を得ている。
1.

食道扁平上皮癌の微小環境を 4 種類に分類した。第 1 群は低酸素環境を特徴とす

る群である。97 症例のうち 60 症例(62%)が該当する。癌細胞の増殖は酸素需要を増加さ
せ、また食道扁平上皮癌に頻度の高い遺伝子変異である TP53 変異はワールブルグ効果に
より解糖速度と乳酸産生を増加させることで低酸素環境を助長する。低酸素環境は一般的
に抗腫瘍免疫を抑制して、また化学療法や放射線療法に対する耐性を獲得させ、臨床転帰
の不良につながると考えられてきた。しかしながら低酸素環境は免疫抑制性に寄与する他
に、免疫賦活的な役割を併せもっており、低酸素により活性化された細胞障害性 T 細胞が
免疫原性細胞死に寄与している可能性も明らかとなった。第 2 群は抗腫瘍免疫が活発に生
じている予後良好な群である。97 症例のうち 20 症例(21%)が該当する。免疫が活発に生じ
ている一方で CD8+ T 細胞の疲弊や免疫チェックポイント分子による抑制も目立ち、第 2
群に対しては免疫チェックポイント阻害薬の有効性が期待される。第 3 群では M2 型マク
ロファージや肥満細胞による抗腫瘍免疫の抑制が目立つ。97 症例のうち 13 症例(13%)が該
当する。リンパ節転移が最も多く予後は不良である。M1 型マクロファージへの再分極や
肥満細胞浸潤の抑制が治療戦略として考慮される。第 4 群は非癌部上皮と近しい微小環境
を有するが、予後の最も不良な群である。97 症例のうち症例のうち 4 症例(4%)が該当す
る。腫瘍抗原として免疫に認識されるゲノム変異数が少なく、適切な抗原提示や引き続く
免疫応答が生じていない可能性がある。
2.

RNA sequencing から得られた情報量をできる限り保ちながら、食道扁平上皮癌に

おいてにおいて重要と考える腫瘍微小環境を視覚的に表示する IMMUGENO_GRAM を作
成した。恣意的な特徴量の選択を避けるため、ランダムフォレストを利用した機械学習に
より特徴量を削減した。IMMUGENO_GRAM は 12 軸からなるレーダーチャートであり、
0~2 時方向ががん免疫サイクルの開始を、 3~4 時方向が抗腫瘍免疫の強さを、 5~11 時方
向が免疫を抑制する微小環境を表現している。
以上、本論文は食道扁平上皮の微小環境に対して RNA sequencing から得られた俯瞰的な知
見を提供している。個別化治療を受ける患者の転帰を予測あるいは評価する際に、本研究
の結果をふまえた患者背景の検討を行うことで、より効果的な治療の適用が期待される。
よって本論文は博士( 医学 )の学位請求論文として合格と認められる。

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Cancer Genome Atlas Research Network; Analysis Working Group: Asan Uni-

versity; BC Cancer Agency; Brigham and Women’s Hospital; Broad Institute; Brown

University; Case Western Reserve University; Dana-Farber Cancer Institute; Duke

University; Greater Poland Cancer Centre; Harvard Medical School; Institute for

124

Systems Biology; KU Leuven; Mayo Clinic; Memorial Sloan Kettering Cancer Center; National Cancer Institute; Nationwide Children’s Hospital; Stanford University;

University of Alabama; University of Michigan; University of North Carolina; University of Pittsburgh; University of Rochester; University of Southern California;

University of Texas MD Anderson Cancer Center; University of Washington; Van

Andel Research Institute; Vanderbilt University; Washington University; Genome Sequencing Center: Broad Institute; Washington University in St. Louis; Genome Characterization Centers: BC Cancer Agency; Broad Institute; Harvard Medical School;

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University; University of North Carolina; University of Southern California Epigenome Center; University of Texas MD Anderson Cancer Center; Van Andel Research Institute; Genome

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