㸦ᵝᘧ㸧

༤ኈㄢ⛬⏝㸦⏥㸧

- 1 - 㸦ᵝᘧ㸧

Ꮫ ఩ ㄽ ᩥ ࡢ ෆ ᐜ ࡢ せ ᪨

బ⸨ ᾈኸ ༳

㸦Ꮫ఩ㄽᩥࡢࢱ࢖ࢺࣝ㸧

HLA class I expression and its alteration by preoperative hyperthermo-chemoradiotherapy in patients with rectal cancer

(⾡๓ ⇕໬Ꮫᨺᑕ⥺⒪ἲࡀ᪋⾜ࡉࢀࡓ┤⭠⒴࡟࠾ࡅࡿHLA class IࡢⓎ⌧࡜ኚ໬)

㸦Ꮫ఩ㄽᩥࡢせ᪨㸧Ꮠ⛬ᗘࠊ$ุ

࠙┠ⓗࠚ

ᚑ᮶ࠊᐟ୺ࡢᢠ⭘⒆ච␿ࡣ⒴἞⒪࡟࠾࠸࡚㔜せ࡞ᙺ๭ࢆᢸࡗ࡚࠾ࡾࠊᵝࠎ࡞⒴࡟࠾࠸࡚Human leukocyte antigen (HLA) class Iࡢ㧗Ⓨ⌧౛ࡣపⓎ⌧౛ࡼࡾࡶணᚋⰋዲ࡛࠶ࡿ࡜ሗ࿌ࡉࢀ࡚࠸ࡿࠋᨺᑕ⥺἞⒪࡟࠾࠸࡚

ࡶࠊHLA class I࡟ࡼࡿ⭘⒆ᢠཎࡢᥦ♧ࡸࠊ⣽⬊㞀ᐖᛶTࣜࣥࣃ⌫㸦Cytotoxic T lymphocyte: CTL㸧࡟ࡼࡿ⭘⒆

⣽⬊ࡢㄆ㆑࣭᤼㝖ࡢࡶࡘᙺ๭ࡀ᫂ࡽ࠿࡟࡞ࡗ࡚ࡁ࡚࠸ࡿࠋᨺᑕ⥺἞⒪ࡢᢠ⭘⒆ຠᯝࡣ୺࡟ࠊDNAᦆയ࡟ࡼ

ࡿ⣽⬊Ṛ࡟ࡼࡾࡶࡓࡽࡉࢀࡿ࡜⪃࠼ࡽࢀ࡚࠸ࡓࡀࠊ㏆ᖺࠊᢠ⭘⒆ຠᯝࡢ୍ࡘ࡜ࡋ࡚ࠊHLA class IࡸCTLࢆ

௓ࡍࡿᢠ⭘⒆ච␿ࡢάᛶ໬ࡀᒁᡤไᚚࡢྥୖ࡟ᐤ୚ࡍࡿ஦ࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋ

ᮏ◊✲࡛ࡣࠊᒁᡤ㐍⾜┤⭠⒴࡟ᑐࡋ⾡๓ ⇕໬Ꮫᨺᑕ⥺἞⒪㸦Hyperthermo-chemoradiotherapy: HCRT㸧ࢆ

᪋⾜ࡋࡓ᳨యࢆ⏝࠸ࠊ἞⒪๓ᚋࡢHLA class IⓎ⌧ࡢኚ໬࡜ࠊணᚋ࡜ࡢ┦㛵࡟ࡘ࠸᳨࡚ウࡋࡓࠋ

࠙ᑐ㇟࡜᪉ἲࠚ

ᑐ㇟ࡣ⩌㤿኱Ꮫ་Ꮫ㒊㝃ᒓ⑓㝔࡟࡚2003ᖺ࠿ࡽ2011ᖺ࡟⾡๓HCRTࢆ᪋⾜ࡋࡓᒁᡤ㐍⾜┤⭠⒴ᝈ⪅78ྡ

࡛ࠊ἞⒪㛤ጞ᫬ᖺ㱋୰ኸ್ࡣ64ṓ㸦33-85ṓ㸧ࠊ἞⒪㛤ጞ᫬ࡢ⮫ᗋ⑓ᮇࡣI : II : III = 4 : 18 : 56㸦TNMศ㢮,

UICC, ➨7∧㸧࡛࠶ࡗࡓࠋ

ᨺᑕ⥺἞⒪ࡣࠊ10MVX⥺ࢆ⏝࠸ࡓ2ࠥ4㛛↷ᑕ࡟ࡼࡾ㦵┙㒊࡬⥲⥺㔞40ࠥ54Gyࢆᢞ୚ࡋࠊྠ᫬ే⏝໬Ꮫ

⒪ἲࡣࠊ74౛࡛5-fluorouracil + Levofolinateࠊ3౛࡛UFT + leucovorinࠊ1౛࡛Capecitabineࢆᢞ୚ࡋࡓࠋ ⇕⒪

ἲࡣThermotron RF-8ࢆ⏝࠸ࠊ㐌1ᅇࠊྜィ2-6ᅇ⾜ࡗࡓࠋHCRT⤊஢࠿ࡽᡭ⾡ࡲ࡛ࡢᮇ㛫ࡢ୰ኸ್ࡣ10㐌㸦1- 54㐌㸧࡛࠶ࡗࡓࠋ

ᑐ㇟ᝈ⪅ࡢHCRT๓⏕᳨᳨య࠾ࡼࡧ⾡ᚋ᳨యࢆ⏝࠸࡚ච␿⤌⧊໬ᏛᰁⰍ㸦㓝⣲ᢠయἲ㸧ࢆ⾜ࡗࡓࠋHLA class IⓎ⌧ࡣࠊHLA class I㝧ᛶ⭘⒆⣽⬊ࡢ๭ྜ࡟ࡼࡾGrade 0㸸10%ᮍ‶ࠊ1㸸10-50 %ࠊ2㸸50-90%ࠊ3㸸90%

௨ୖࡢ4ẁ㝵࡛ホ౯ࡋࡓࠋணᚋ࡜ࡢ┦㛵࡟ࡘ࠸࡚ࡣࠊGrade0ࠊ1ࢆపⓎ⌧⩌ࠊGrade2ࠊ3ࢆ㧗Ⓨ⌧⩌࡜ࡋ᳨࡚

ウࡋࡓࠋ

࠙⤖ᯝࠚ

HLA class IⓎ⌧ࡣࠊHCRT๓ࡢ᳨య࡛ࡣ Grade 0㸸1㸸2㸸3 ࡀࡑࢀࡒࢀ 19㸸58㸸1㸸0౛࡛࠶ࡾࠊHCRTᚋ ࡢᡭ⾡᦬ฟ᳨య࡛ࡣ Grade 0㸸1㸸2㸸3 ࡀࡑࢀࡒࢀ 6㸸27㸸7㸸12౛࡛࠶ࡗࡓࠋHCRT࡟ࡼࡾ⑓⌮Ꮫⓗ᏶඲

ዌຌࢆᚓࡓ26౛ࡢᡭ⾡᦬ฟ᳨యࡣࠊ⭘⒆⤌⧊ࡢᾘኻࡢࡓࡵホ౯࡛ࡁ࡞࠿ࡗࡓࠋࡲࡓࠊHCRT࡟ࡼࡿHLA class IⓎ⌧ࡢኚ໬ࡣⓎ⌧ቑᙉࠊ୙ኚࠊⓎ⌧పୗࡀࡑࢀࡒࢀ29ࠊ27ࠊ3౛࡛ࠊ⾡ᚋ᳨య࡛᭷ព࡟ቑᙉࡋ࡚࠸ࡓࠋ

HCRT๓᳨య࡛ࡣ78౛୰77౛ࡀపⓎ⌧⩌࡛࠶ࡾࠊணᚋ࡜ࡢ┦㛵ࡣホ౯࡛ࡁ࡞࠿ࡗࡓࠋ⾡ᚋ᳨య࡟࠾ࡅࡿ5 ᖺ඲⏕Ꮡ⋡㸦OS㸧ࠊᒁᡤไᚚ⋡㸦LC㸧ࠊ↓㌿⛣⏕Ꮡ⋡㸦DMFS㸧ࡣࡑࢀࡒࢀࠊపⓎ⌧⩌࡛76%, 94%, 76%ࠊ 㧗Ⓨ⌧⩌࡛79%, 74%, 79%࡛࠶ࡾࠊ࠸ࡎࢀࡶ᭷ពᕪࢆㄆࡵ࡞࠿ࡗࡓࠋ56౛ࡢIIIᮇ⑕౛࡟㝈ࡗ᳨࡚ウࡍࡿ࡜ࠊ OS, LC, DMFSࡣࡑࢀࡒࢀࠊపⓎ⌧⩌࡛70%, 100%, 70%ࠊ㧗Ⓨ⌧⩌࡛92%, 77%, 85%࡛࠶ࡾࠊOS࡜DMFSࡣ 㧗Ⓨ⌧⩌࡛⤒㐣Ⰻዲ࡞ഴྥࢆㄆࡵࡓ (p=0.13, p=0.28)ࠋ୍᪉LCࡣ㧗Ⓨ⌧⩌ࡀ᭷ព࡟୙Ⰻ࡛࠶ࡗࡓࠋከኚ㔞ゎ

༤ኈㄢ⛬⏝㸦⏥㸧

- 2 -

ᯒ࡛ࡣHLA class IⓎ⌧ࡣ࠸ࡎࢀ࡟ࡶ᭷ព࡞┦㛵ࢆㄆࡵ࡞࠿ࡗࡓࠋ

࠙⪃ᐹࠚ

Speetjensࡽࡢ┤⭠⒴ᝈ⪅࡛ࡢHLA class IⓎ⌧࡜↷ᑕࡢ㛵ಀ࡟ࡘ࠸࡚ࡢሗ࿌࡛ࡣࠊ㠀↷ᑕ⩌࡛ࡶHLA class I 㧗Ⓨ⌧㸦㝧ᛶ⋡50%௨ୖ㸧ࡢ㢖ᗘࡣ50%௨ୖ࡛࠶ࡾࠊᮏ◊✲࡛ࡣࠊHCRT๓᳨య࡛ࡢ㧗Ⓨ⌧ࡀ1౛㸦1%㸧ࡢ

ࡳ࡛࠶ࡗࡓࠋࡇࡢ┦㐪ࡢཎᅉ࡜ࡋ࡚ࠊᰁⰍ࡟⏝࠸ࡓ୍ḟᢠయࡢ㐪࠸ࡸࠊุᐃ⢭ᗘࡢ㝈⏺ࡀᙳ㡪ࡋࡓྍ⬟ᛶ ࡀ⪃࠼ࡽࢀࡿࠋࡲࡓIIIᮇ⑓ኚࡢ๭ྜࡀࠊᮏ◊✲࡛ࡣ72%ࠊSpeetjensࡽࡢሗ࿌࡛ࡣ35%࡛࠶ࡾࠊ㐍⾜⒴࡯࡝ච

␿᢬ᢠᛶࡢഴྥ࡟࠶ࡿ࡜ࡍࡿ ”Immunoediting” ࡢᴫᛕࡀᙳ㡪ࡋ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡿࠋ

ᨺᑕ⥺࡟ࡼࡿHLA class IⓎ⌧ࡢቑᙉ࡟ࡘ࠸࡚ࡣࠊin vitro࡛ࡢ◊✲ࡣሗ࿌ࡀ࠶ࡿࡀࠊ⮫ᗋሗ࿌ࡣㄆࡵࡽࢀ

࡞࠸ࠋSpeetjensࡽࡣ┤⭠⒴ᝈ⪅࡟࠾࠸࡚↷ᑕ⩌࡜㠀↷ᑕ⩌ࢆẚ㍑ࡋࠊ୧⩌㛫࡛ࡢⓎ⌧࡟᭷ពᕪࢆㄆࡵ࡞࠿

ࡗࡓ࡜ሗ࿌ࡋ࡚࠸ࡿࠋ୍᪉ࠊᮏ◊✲࡛ࡣࠊྠ୍⑕౛࡟࠾࠸࡚HCRT࡟ࡼࡿHLA class IࡢⓎ⌧ࡀቑᙉࡍࡿࡇ࡜

ࢆ᫂ࡽ࠿࡟ࡋࡓࠋ↷ᑕ࡟ࡼࡿHLA class IⓎ⌧ࡢቑᙉ࡟ࡘ࠸࡚Reitsࡽࡣࠊࣄࢺ࣓ࣛࣀ࣮࣐⣽⬊ࡸࠊ࣐࢘ࢫ࡟

⛣᳜ࡋࡓ⭈⣽⬊࠾ࡼࡧ⓶ୗ⤌⧊࡟࠾࠸࡚⥺㔞౫Ꮡⓗ࡟HLA class IⓎ⌧ࡀቑᙉࡍࡿ஦ࢆ᫂ࡽ࠿࡟ࡋࡓࠋ௒ᚋ ࡢࡉࡽ࡞ࡿ◊✲࡟ࡼࡾࠊHLA class IⓎ⌧ࡢపୗ࡟ࡼࡾච␿᢬ᢠᛶࢆ⋓ᚓࡋࡓ⭘⒆࡟ᑐࡋ࡚ࠊᨺᑕ⥺἞⒪ࢆ

ྵࡴ἞⒪᪉ἲ࡜ච␿⒪ἲࡢే⏝ࡀ᭷ຠ࡜࡞ࡿྍ⬟ᛶࡀ♧၀ࡉࢀࡿࠋ

ࡲࡓࠊ ⇕⒪ἲࡸ໬Ꮫ⒪ἲ࡟ࡼࡿHLA class IⓎ⌧ቑᙉࡶሗ࿌ࡉࢀ࡚࠸ࡿࠋᮏ◊✲ࡣHCRT࡟ࡼࡾHLA class IⓎ⌧ࡀ᭷ព࡟ቑᙉࡍࡿࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋࡓึࡵ࡚ࡢሗ࿌࡛࠶ࡿࡀࠊᮏ◊✲ࡢ἞⒪ࡣ↷ᑕࠊ ⇕⒪ἲࠊ

໬Ꮫ⒪ἲࡢే⏝࡛࠶ࡾࠊ୕⪅ࡀ┦஌ⓗ࡟HLA class IⓎ⌧ࢆቑᙉࡉࡏࡓྍ⬟ᛶࡀ࠶ࡿࠋࡑࡢࡓࡵࠊ࣓࢝ࢽࢬ

࣒ࢆ᫂ࡽ࠿࡟ࡍࡿࡓࡵ࡟ࡣࠊࡼࡾヲ⣽࡞◊✲ࡀᚲせ࡛࠶ࡿࠋ

ᮏ◊✲ࡣࡇࢀࡲ࡛ࡢሗ࿌࡜ࡣ␗࡞ࡾࠊHLA class I㧗Ⓨ⌧⩌࡛ࡢඃ఩࡞ணᚋࡢᨵၿࡣㄆࡵ࡞࠿ࡗࡓࠋࡇࡢ ཎᅉ࡜ࡋ࡚ࡣࠊ⮫ᗋ࡛ࣞ࣋ࣝࡢணᚋ࡬ࡢᙳ㡪ࡣHLA class Iࡸࡑࢀࢆ௓ࡋࡓච␿స⏝ࡼࡾࡶᡭ⾡ࡢᙳ㡪ࡀᙉ

࠸࡜⪃࠼ࡽࢀࡿࡇ࡜ࠊࡲࡓච␿ࡣ㠀ᖖ࡟」㞧࡞⣔⤫࡛࠶ࡾHLA class I࡟㛵ࡍࡿ཯ᛂࡔࡅ࡛ࡣணᚋࡢᨵၿ࡟

ࡣ୙༑ศ࡛࠶ࡿࡇ࡜ࠊ56౛࡜࠸࠺⑕౛ᩘࡀ᭷ពᕪࢆ᳨ウࡍࡿ࡟ࡣ୙༑ศ࡛࠶ࡗࡓྍ⬟ᛶ࡞࡝ࡀ⪃࠼ࡽࢀࡿࠋ ࡑࡢࡓࡵࠊHLA class IⓎ⌧࡜┤⭠⒴ᝈ⪅ࡢணᚋ࡜ࡢ㛵ಀࢆ᫂ࡽ࠿࡟ࡍࡿࡓࡵ࡟ࡣࠊࡉࡽ࡞ࡿ◊✲ࡀồࡵࡽ

ࢀࡿࠋ

⤖ㄽ࡜ࡋ࡚ࠊ┤⭠⒴ࡢHLA class IⓎ⌧ࡣHCRT࡟ࡼࡾ᭷ព࡟ஹ㐍ࡋࡓࡀࠊணᚋ࡟ࡣᙳ㡪ࡋ࡞࠿ࡗࡓࠋ