JAK2V617F変異を伴う骨髄増殖性腫瘍の 変異クローンの拡大はPD-1陽性CD8陽性T細胞の減少を伴う
JAK2V617F変異を伴う骨髄増殖性腫瘍患者の血液では，野生型JAK2遺伝子血球（正常造血細胞由来）と，JAK2V617F変異遺伝子をもつ血球（JAK2V617F変異造血細胞由来）の両者が混在する．そして近年，JAK2V617F変異血球に対する抗腫瘍免疫の存在と，免疫チェックポイント分子の関与が示唆されている．今回我々は，JAK2V617F変異クローンの拡大と，血球上に発現する免疫チェックポイント分子の関係性を明らかにする為に，患者26名の末梢血液を用い，JAK2V617F変異血球クローンの割合（JAK2V617F allele burden），PD1陽性CD8陽性T細胞群比率，血小板上のP...
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| Published in | 岩手医学雑誌 Vol. 73; no. 4; pp. 165 - 176 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
岩手医学会
2021
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| Online Access | Get full text |
| ISSN | 0021-3284 2434-0855 |
| DOI | 10.24750/iwateishi.73.4_165 |
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| Abstract | JAK2V617F変異を伴う骨髄増殖性腫瘍患者の血液では，野生型JAK2遺伝子血球（正常造血細胞由来）と，JAK2V617F変異遺伝子をもつ血球（JAK2V617F変異造血細胞由来）の両者が混在する．そして近年，JAK2V617F変異血球に対する抗腫瘍免疫の存在と，免疫チェックポイント分子の関与が示唆されている．今回我々は，JAK2V617F変異クローンの拡大と，血球上に発現する免疫チェックポイント分子の関係性を明らかにする為に，患者26名の末梢血液を用い，JAK2V617F変異血球クローンの割合（JAK2V617F allele burden），PD1陽性CD8陽性T細胞群比率，血小板上のPD-L1発現レベル，を評価した．その結果，JAK2V617F allele burdenはPD1陽性CD8陽性T細胞群比率と有意な逆相関を示した．一方で，血小板上のPD-L1発現量は，JAK2V617F allele burdenやPD1陽性CD8陽性T細胞群と明らかな相関を認めなかった．結論として，JAK2V617F血球のクローンサイズの増加とともに，PD1陽性CD8陽性T細胞群は減少する．一方で血小板上のPD-L1発現量はJAK2V617F変異血球や抗腫瘍免疫細胞の動態を反映しない． |
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| AbstractList | JAK2V617F変異を伴う骨髄増殖性腫瘍患者の血液では，野生型JAK2遺伝子血球（正常造血細胞由来）と，JAK2V617F変異遺伝子をもつ血球（JAK2V617F変異造血細胞由来）の両者が混在する．そして近年，JAK2V617F変異血球に対する抗腫瘍免疫の存在と，免疫チェックポイント分子の関与が示唆されている．今回我々は，JAK2V617F変異クローンの拡大と，血球上に発現する免疫チェックポイント分子の関係性を明らかにする為に，患者26名の末梢血液を用い，JAK2V617F変異血球クローンの割合（JAK2V617F allele burden），PD1陽性CD8陽性T細胞群比率，血小板上のPD-L1発現レベル，を評価した．その結果，JAK2V617F allele burdenはPD1陽性CD8陽性T細胞群比率と有意な逆相関を示した．一方で，血小板上のPD-L1発現量は，JAK2V617F allele burdenやPD1陽性CD8陽性T細胞群と明らかな相関を認めなかった．結論として，JAK2V617F血球のクローンサイズの増加とともに，PD1陽性CD8陽性T細胞群は減少する．一方で血小板上のPD-L1発現量はJAK2V617F変異血球や抗腫瘍免疫細胞の動態を反映しない． |
| Author | 小宅, 達郎 阿保, 亜紀子 佐藤, 剛 関, 裕葵 佐々木, 了政 前田, 峻大 古和田, 周吾 伊藤, 薫樹 岡野, 良昭 宮島, 真理 |
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| References_xml | – reference: Wang JC, Chen C, Kundra A, et al.: Programmed cell death receptor （PD-1） ligand （PD-L1） expression in Philadelphia chromosome-negative myeloproliferative neoplasms. Leuk Res 79, 52-59. 2019. – reference: Braun LM and Zeiser R: Immunotherapy in myeloproliferative diseases. Cells 9, cells9061559, 2020. – reference: Jerby-Arnon L, Shah P, Cuoco MS, et al.: A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984-997, 2018. – reference: Wang JC, Kundra A, Andrei M, et al.: Myeloid-derived suppressor cells in patients with myeloproliferative neoplasm. Leuk Res 43, 39-43, 2016. – reference: Tam CS, Kantarjian H, Cortes J, et al.: Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. J Clin Oncol 27, 5587-5593, 2009. – reference: Jansen CS, Prokhnevska N, Master VA, et al.: An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465-470, 2019. – reference: Lange T, Edelmann A, Siebolts U, et al.: JAK2 V617F allele burden in myeloproliferative neoplasms one month after allogeneic stem cell transplantation significantly predicts outcome and risk of relapse. Haematologica 98, 722-728, 2013. – reference: Rolfes V, Idel C, Pries R, et al.: PD-L1 is expressed on human platelets and is affected by immune checkpoint therapy. Oncotarget 9, 27460-27470, 2018. – reference: Borowczyk M, Wojtaszewska M, Lewandowski K, et al.: The JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms. Thromb Res 135, 272-280, 2015. – reference: Barbui T, Thiele J, Gisslinger H, et al.: The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J 8,15, 2018. – reference: Kirito K, Koike M, Noguchi M, et al.: A novel quantitative JAK2 V617F detection kit: prospective clinical performance study comparing MPN patients and healthy subjects. Rinsho Ketsueki 59, 669-674, 2018. – reference: Kovacsovics-Bankowski M, Kelley TW, Efimova O, et al.: Changes in peripheral blood lymphocytes in polycythemia vera and essential thrombocythemia patients treated with pegylated-interferon alpha and correlation with JAK2V617F allelic burden. Exp Hematol Oncol 5, 28, 2016. – reference: Cabrita R, Lauss M, Sanna A, et al.: Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561-565, 2020. – reference: Edahiro Y, Morishita S, Takahashi K, et al.: JAK2 V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan. Int J Hematol 99, 625-634, 2014. – reference: Vannucchi AM, Antonioli E, Guglielmelli P, et al.: MPD Research Consortium. Prospective identification of high-risk polycythemia vera patients based on JAK2 （V617F） allele burden. Leukemia 21, 1952-1959, 2007. – reference: Im SJ and Ha SJ: Re-defining T-Cell Exhaustion: Subset, Function, and Regulation. Immune Netw 20, 2, 2020. – reference: Skov V, Larsen TS, Thomassen M, et al.: Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res 36, 1387-92, 2012. – reference: Morishita S, Komatsu N, Kirito K, et al.: Alternately binding probe competitive PCR as a simple, cost-effective, and accurate quantification method for JAK2 V617F allele burden in myeloproliferative neoplasms. Leuk Res 35, 1632-1636, 2011. – reference: Prestipino A, Emhardt AJ, Aumann K, et al.: Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med 10, 7729, 2018. – reference: Helmink BA, Reddy SM, Gao J, et al.: B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549-555, 2020. – reference: Dan K, Yamada T, Kimura Y, et al.: Japanese elderly leukemia and lymphoma study group. Clinical features of polycythemia vera and essential thrombocythemia in Japan: retrospective analysis of a nationwide survey by the Japanese elderly leukemia and lymphoma study group. Int J Hematol 83, 443-449, 2006. – reference: Shirane S, Araki M, Morishita S, et al.: Consequences of the JAK2 V617F allele burden for the prediction of transformation into myelofibrosis from polycythemia vera and essential thrombocythemia. Int J Hematol 101, 148-153, 2015. – reference: Hara R, Kawada H, Kikuti YY, et al.: A case of JAK2 V617F-positive essential thrombocythemia where allele burden was reduced by a PD-1 inhibitor. Int J Hematol 113. 606-610, 2021. – reference: Romano M, Sollazzo D, Trabanelli S, et al.: Mutations in JAK2 and calreticulin genes are associated with specific alterations of the immune system in myelofibrosis. Oncoimmunology 6, e1345402, 2017. – reference: Nishanth G, Wolleschak D, Fahldieck C, et al.: Gain of function in Jak2V617F-positive T-cells. Leukemia 31, 1000-1003, 2017. |
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| Title | JAK2V617F変異を伴う骨髄増殖性腫瘍の 変異クローンの拡大はPD-1陽性CD8陽性T細胞の減少を伴う |
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