28th EHA Congress Travel Award 受賞レポート　末原　泰人

名前：末原 泰人【筑波大学附属病院 血液内科】
発表形式：Oral

Title:

The genetic subtypes and tumor microenvironments are associated with distinct outcomes in peripheral T-cell lymphoma

Authors:

Yasuhito Suehara ¹, Kana Sakamoto ², Manabu Fujisawa ³, Kota Fukumoto ⁴, Yoshiaki Abe ⁵, Kenichi Makishima ⁵, Sakurako Suma ⁵, Tatsuhiro Sakamoto ^{1, 3}, Keiichiro Hattori ^{1, 3}, Yumiko Maruyama ¹, Takayasu Kato ^{1, 3}, Naoki Kurita ^{1, 3}, Yasuhisa Yokoyama ^{1, 3}, Hidekazu Nishikii ^{1, 3}, Naoshi Obara ^{1, 6}, Takeshi Sugio ⁷, Koji Kato ⁸, Koichi Akashi ⁸, Kosei Matsue ⁹, Kentaro Narita ⁹, Kengo Takeuchi ², Naoya Nakamura ¹⁰, Kenichi Chiba ¹¹, Yuichi Shiraishi ¹¹, Seishi Ogawa ¹², Shigeru Chiba ^{1, 3}, and Mamiko Sakata-Yanagimoto ^{1, 3, 13}

Affiliations:

1. Dept. of Hematology, Univ. of Tsukuba Hospital, Tsukuba, Japan
2. Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
3. Dept. of Hematology, Faculty of Medicine, Univ. of Tsukuba, Tsukuba, Japan
4. Dept. of Hematology, Ageo General Central Hospital, Saitama, Japan
5. Dept. of Hematology, Graduate School of Comprehensive Human Sciences, Univ. of Tsukuba, Tsukuba, Japan
6. Dept. of Medical Sciences, Faculty of Medicine, Univ. of Tsukuba, Tsukuba, Japan
7. Dept. of Medicine, Division of Oncology, Stanford Univ., Stanford, United States
8. Dept. of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
9. Division of Hematology/Oncology, Dept. of Internal Medicine, Kameda Medical Center, Kamogawa, Japan
10. Dept. of Pathology, Tokai Univ. School of Medicine, Isehara, Japan
11. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The Univ. of Tokyo, Tokyo, Japan
12. Dept. of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto Univ., Kyoto, Japan
13. Division of Advanced Hemato-Oncology, Transborder Medical Research Center, Univ. of Tsukuba, Tsukuba, Japan

Abstract:

Background: Emerging evidence suggests the prognostic impact of the tumor microenvironment （TME） in peripheral T-cell lymphomas （PTCLs）.

Aims: To better understand PTCL pathobiology, we performed an integrative multi-omics study to explore the genetic subtypes and the TME signatures of PTCLs, especially nodal T-follicular helper T-cell lymphomas （nTFHLs） and PTCL, not otherwise specified （PTCL-NOS）.

Methods: We performed whole-exome sequencing of 92 nTFHLs and 37 PTCL-NOSs, a total of 129 cases, on the Illumina HiSeq platform. Ninety-two nTFHLs included 85 angioimmunoblastic T-cell lymphomas （AITLs）, four nPTCL with TFH phenotypes, two follicular T-cell lymphomas, and one unclassifiable nTFHL. Mapping, mutation calling, and structural variants detection were performed using Genomon-pipeline. Copy number alterations were analyzed using GATK tools. Genetic drivers recurrently observed in more than 5 cases were integrated using non-negative matrix factorization consensus clustering （NMF）. We estimated the proportion of immune cell fractions from bulk RNA sequencing data （n＝57） using CIBERSORTx and classified the TME signatures using hierarchical clustering.

Results: NMF clustering analysis revealed three genetic subtypes within our cohort, except for 10 cases lacking recurrent genetic abnormalities （denoted as cluster 0）. Clusters 1 and 3 （C1 and C3） mostly included nTFHL cases （82％ and 91％, respectively）, while nTFHL pathology contributed to 32％ of cluster 2 （C2）. C2 was characterized by TP53 mutation, CDKN2A loss, PTEN loss, and chromosomal instability, corresponding to the previously described GATA3-PTCL subtype （Watatani, 2019; Tayla, 2019）. IRF4 gain, recognized as a poor prognostic feature of PTCL, was also enriched in C2. The frequencies of genomic alterations involved in TCR-signaling/NF kappa-B, immune surveillance, PI3K/AKT/mTOR, and tumor suppressor were significantly higher in C2 than in the other subtypes. C1 and C3 shared TFH-related genomic alterations, but C3 had significantly higher frequencies of chromosome （Chr） 5 gain, Chr 21 gain, RHOA, IDH2, and CD28 mutations. A higher frequency of rash and higher C-reactive protein levels than the other AITLs characterized C3-AITL. Pairwise association analysis of genomic alterations revealed that multiple TET2 mutations, rather than a single TET2 mutation, significantly co-occurred with IDH2 and RHOA mutations. Compared to C1, significantly inferior survival was observed in C2 （hazard ratio, 2.52; 95％CI, 1.37-4.63; Fig. A） and C3 （hazard ratio, 2.14; 95％CI, 1.17-3.89）. The TME signatures were divided into CD4 naïve T-cell type, M2-macrophage/CD4 memory T-cell type, and B-cell type. The M2 macrophage signature was significantly associated with shorter overall survival than the B-cell signature （HR: 8.73, 95％CI 2.32-32.8; Fig. B）. The C2-genetic subtype was significantly associated with the M2-macrophage signature compared to C1 （64.3％ vs. 7.6％, p＝0.006, with BH correction; Fig. C）. mTORC1 signaling was enriched in the M2-macrophage signature compared to CD4 naïve and B-cell signatures. Furthermore, AKT and PI3K/mTOR inhibitors were active for the GATA3-PTCL-like cell line established from the PTCL mouse model （Fukumoto, 2020）.

Summary/Conclusion: C1 and C3, the two major nTFHL genetic subtypes, showed differences in clinical features and survival outcomes. Poor prognosis subtypes discovered using different approaches, the C2 genetic subtype and the M2-macrophage TME signature, were significantly associated. AKT and PI3K/mTOR inhibitors were therapeutic candidates for this subtype of PTCL.

EHA2023参加レポート

European Hematology Association（EHA）2023 Hybrid Congressへの参加にあたって日本血液学会EHA Travel Awardに御採択いただき，ご援助賜りましたこと，誠にありがとうございました。EHAへの参加は実に8年ぶりであり，楽しみにしておりました。台湾経由でフランクフルトに到着すると，すっかり夏の陽気であり，日は長く，日没は21時30分頃でした。会場のメッセの周辺には，国際金融の中心地らしく多数の高層ビルが立ち並ぶ一方，地下鉄で少し移動するとアルトシュタットには大聖堂や市庁舎など歴史的建造物が立ち並んでいました。

COVID-19流行開始後の学会がハイブリッド形式になって久しいですが，現地開催/バーチャル形式双方の良さがあり，大きな学会はハイブリッドが今後も継続されるのでしょう。時間が重複してしまって参加できなかったセッションをオンデマンドで視聴できるのは，本当に助かります。一方で思いがけない出会いや，些細な質問やコミュニケーション，ネットワーキングは現地参加でないと難しいことです。CAR-Tやリンパ腫領域のBiTE，骨髄腫のBCMA関連演題が百花繚乱でした。また，今回ICC分類と5th WHO分類が分かれてしまいましたが，lymphoid，myeloidの双方で解説や分類のPro/Conがなされており，二つの新分類の理解の助けとなりました。

私自身は，血管免疫芽球性T細胞リンパ腫（AITL）を中心とした末梢性T細胞性リンパ腫（PTCL）を対象にマルチオミクス解析を行い，ゲノム異常の亜分類と腫瘍微小環境を検討した研究について発表いたしました。AITLを主としたTFHリンパ腫は，多くは2つのゲノム異常サブタイプに大別され，予後や表現型が異なっていることを見出しました。また，主にPTCL-NOSからなるゲノム異常に基づく予後不良の一群（CDKN2A欠失，TP53変異，多数のコピー数異常）と腫瘍微小環境に基づく予後不良群（マクロファージ浸潤型）はそれぞれ既報を追認するものでしたが，統合解析によりこれら二群が有意に関連していることを見出しました。発表後には，様々な質問や意見をいただき，今後の研究遂行・論文執筆において大変参考になりました。

大変貴重な機会を与えて下さった日本血液学会事務局，国際委員の方々，日頃より研究のご指導をいただいております坂田麻実子先生，千葉滋先生に心より感謝申し上げます。この経験をもとに日々の診療・研究に邁進してまいります。