HMR Hun Sik Kim Natural Killer Cell and Cancer Immunotherapy 본론 1. 항암치료연구동향암은현대의학이정복하지못한대표적인난치성질환가운데하나이다. 전세계적으로연간 3천만명의암환자가증가하고있으며한국인의사망원인 1위는지속적으로암이

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1 자연살해세포와항암면역치료 김헌식 pissn X eissn 울산대학교의과대학대학원의학과 Natural Killer Cell and Cancer Immunotherapy Hun Sik Kim Department of Medicine, Graduate School, University of Ulsan College of Medicine, Seoul, Korea Cancer remains the leading cause of death worldwide despite intense efforts in developing innovative treatments. Current approaches in cancer therapy are mainly directed to a selective targeting of cancer cells to avoid potential side effects associated with conventional therapy. In this respect, Natural killer (NK) cells have gained growing attention and are now being considered as promising therapeutic tools for cancer therapy owing to their intrinsic ability to rapidly recognize and kill cancer cells, while sparing normal healthy cells. NK cells play a key role in the first line of defense against transformed and virus-infected cells. NK cells sense their target through a whole array of receptors, both activating and inhibitory. Functional outcome of NK cell against target cells is determined by the balance of signals transmitted from diverse activating and inhibiting receptors. Despite significant progress made in the role of NK cells attack as a pivotal sentinel in tumor surveillance, the molecular has been that regulate NK cell responses remain unclear, which restricts the use of NK cells as a therapeutic measure. Accordingly, current efforts for NK cellbased cancer therapy have largely relied on the strategies that are based on the manipulation of inhibitory receptor function. However, if we better understand the mechanisms governing NK cell activation, including those mediated by diverse activating receptors, this knowledge can be applied to the development of optimal design for cancer immunotherapy by targeting NK cells. Correspondence to: Hun Sik Kim 우 , 서울시송파구아산병원길 86, 울산대학교의과대학아산생명과학연구원 1 관 10 층 University of Ulsan College of Medicine, 1-kgwan 10th floor, Asan Biomedical Research Center, 86 Asanbyeongwongil, Songpa-gu, Seoul , Korea Tel: Fax: hunkim@amc.seoul.kr Received 12 November 2012 Revised 4 January 2013 Accepted 9 January 2013 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Key Words: Killer Cells, Natural; Immunotherapy; Receptors, Immunologic; Activation Analysis 서론암은한국인에서단일질환으로가장높은사망률을보이며더불어막대한사회적경제적부담을유발하는질환이다. 전통적인치료방법인수술, 방사선, 혹은항암제투여의경우비록단기적으로치료효과를보이나많은부작용과함께장기적으로면역력저하에의한암의재발등심각한문제점들을내포하고있다. 최근기존항암치료법의한계를극복, 보완할수있는치료법중의하나로면역세포치료제가각광을받고있다. 다양한면역세포중자연살해세포 (natural killer cell, NK cell) 의경우직접적으로암의발생, 증식, 전이및재발을막는데효과적이라는사실이밝혀져최근주목받고있다 [1]. 현재자연살해세포를이용해암을치료하려는다양한임상연구들이시도되고있으며유망한결과들이보고되고있다. 그러나자연살해세포활성화기전이명확하지않아자연살해세포를이용한치료법은매우제한적인방법들에초점이맞추어져있다 [2]. 따라서자연살해세포활성화기전에대한정확한이해가수반된다면좀더효과적인방법들이개발될것으로기대된다. 이글에서는항암치료에있어자연살해세포의장점, 자연살해세포의활성화기전, 자연살해세포를이용한치료연구동향을중심으로기술하였다 Hanyang University College of Medicine 59

2 HMR Hun Sik Kim Natural Killer Cell and Cancer Immunotherapy 본론 1. 항암치료연구동향암은현대의학이정복하지못한대표적인난치성질환가운데하나이다. 전세계적으로연간 3천만명의암환자가증가하고있으며한국인의사망원인 1위는지속적으로암이차지하고있다. 아직까지기존의항암치료는외과적수술, 항암제투여, 방사선조사가대세를이루고있다. 그러나세포독성등심각한부작용과암의전이 재발등으로인해새로운치료법의개발이절실히요구되고있다. 실제로수술, 항암제투여와방사선조사는체력의약화와면역력저하를초래하며, 이러한처치후몸속에남아있는암세포의재발및전이를촉진할가능성이크다. 암으로사망하는환자들의대부분은암이재발되어사망한다. 이에따라최근개발되는암치료제의경우부작용없이선택적으로암세포를파괴하는데초점이맞춰지고있다. 현재주목받고있는항암치료법의연구방향은일차적으로암세포를기존치료방법으로최소화시킨후잔존해있는암을세포면역요법등에의해완전히제거하는것을목표로한다. 최근암을치료하기위한세포면역요법으로암세포를선택적으로파괴하는자연살해세포, 세포독성 T세포 (cytotoxic T cell), 그리고면역반응유도에중추적인역할을하는수지상세포 (dendritic cell, DC) 가주목받고있다. 세포면역요법은인체의면역감시 (immune surveillance) 기능에관여하는세포를활성화시킴으로써인체가스스로암세포를제거하게하는인체면역원리를이용한것이다. 식조절에도중요한역할을함이밝혀지고있다 [1]. 더불어자연살해세포는수지상세포, 대식세포 (macrophage), T세포와의직접적상호작용및시토카인을통한간접적상호작용을통해면역반응을조절하는데도핵심적인역할을한다. 이를통해염증질환, 자가면역질환및천식등각종난치성질환의발병에도자연살해세포가중요한역할을하고있음이속속밝혀지고있다. 2) 항암면역치료에있어자연살해세포의장점자연살해세포는항암면역치료제개발측면에서다른면역세포들에비해많은장점을가진다. 자연살해세포는암세포의발생, 증식, 전이를억제할뿐만아니라암의재발에가장중요한암줄기세포를효과적으로제거할수있다 [6]. 암줄기세포는항암제와방사선치료에강한저항성을가지며일단임상적으로암이완치된뒤에도수년후에다른부위로암이전이 재발되는데중요한역할을한다 [7,8]. 즉일시적으로관해 (remission) 에도달한암환자가수개월또는수년후에재발하는것을종종보게되는데, 이것은항암제의공격에살아남은암줄기세포가잠복상태에있다가다시활발히증식 분화하기때문이다. 따라서암줄기세포를제거한다면암의재발을막고효과적으로치료할수있는가능성이크며자연살해세포는이러한측면에서큰장점을가진다 [9,10]. 더욱이여러임상연구에서친족이나정상인에서분리한자연살해세포를환자에도입했을때다른면역세포와달리면역거부반응이극히적어세포치료제로개발시에도매우안전하다 [11]. 2. 항암면역치료와자연살해세포다양한항암면역세포중자연살해세포는직접적으로암세포의발생, 증식, 전이를억제할뿐만아니라암의재발에중요한암줄기세포 (cancer stem cell) 를효과적으로제거할수있어항암면역치료제개발측면에서많은장점을가지고있다. 1) 자연살해세포 (natural killer cell) 자연살해세포는선천면역세포중의하나로암세포에대해선택적인세포독성을보이는세포다 [3]. 자연살해세포는다른면역세포와달리암세포를즉각적으로감지하여바로제거할수있는데이것은자연살해세포표면에존재하는다양한면역수용체 (immune receptor) 를통해암세포와정상세포를구분할수있기때문이다 [4,5]. 많은암환자의경우자연살해세포의수나항암활성에결함이발견되고있으며자연살해세포의기능이상은이러한암의발생과밀접한관련을가지고있다고알려져있다. 또한자연살해세포는 IFN-γ 나 TNF-α 같은시토카인 (cytokine) 생성을통해염증및면역반응을조절하는데핵심적인역할을한다. 많은연구를통해자연살해세포가암세포및바이러스감염세포를제거하는데핵심적인역할을함이규명되었으며또한골수이식, 태아의착상및생 3. 자연살해세포활성화와면역수용체의역할자연살해세포는항원특이적수용체가없는대신활성을유도하거나억제하는 germ-line encoding된다양한면역수용체를발현한다. 현재많은자연살해세포수용체들이발견되고그역할이규명되고있으나계속새로운수용체의존재및그역할이보고되고있는상황이다. 자연살해세포는이들수용체를통해표적세포 (target cell) 를인식하고이로써유도되는종합적인신호전달균형에의해그활성이조절된다 [12-14]. 따라서자연살해세포의활성화기전을이해하기위해서는이런다양한수용체의조합에의해자연살해세포의활성이어떻게조절되는지이해하는것이필수적이다. 1) 자연살해세포활성화 (activation) 수용체자연살해세포활성화수용체는주로표적세포가비정상상태에있을때발현하는 ligand들을인식한다. 대표적으로 natural killer group 2 member D (NKG2D) 수용체의경우 DNA 손상, 암발생, 감염시발현이증가되는세포내분자인 UL16 binding proteins (ULBPs) 와 MICA/B ( 사람 ), RAE1, H60, MULT1 ( 생쥐 ) 을감지한다 [15-17]. 이외에도사람의 NKp46, NKp44, NKp30, 2B4, DNAM- 1 활성화수용체등이암의발생을감지하여제거하는데중요한역 60

3 김헌식 자연살해세포와항암면역치료 HMR 할을한다 [18-22]. 이중 NKp46와 NKp44의세포내 ligand는아직규명되지않았으며 NKp30는 B7-H6 [23], 2B4는 CD48 [24], DN- AM-1 은 PVR과 Nectin-2 [25] 를 ligand로인식한다. 또한 B세포에서유래된항체가표적세포의항원을인식하여결합하는경우이런표적세포는자연살해세포의 low-affinity Fc 수용체인 CD16 에의해감지되며강력한활성이유도되는 antibody-dependent cellular cytotoxicity (ADCC) 에의해효과적으로제거된다 [4,13]. 2) 자연살해세포억제 (inhibitory) 수용체자연살해세포의억제수용체는주로표적세포의표면에항시적으로발현되는세포내분자의존재유무를인지한다 [5,26]. 대표적으로자연살해세포는 MHC Class I에특이적인억제수용체를발현하는데만일표적세포가 MHC Class I이결핍되어있다면자연살해세포의활성을억제할수있는신호가전달되지못한다. 그결과자연살해세포는 missing self 된표적세포를감지하여제거한다 [3]. 표적세포의 MHC Class I은많은경우암의발생이나감염같은스트레스에의해그발현이감소된다. 자연살해세포에서발현되는 MHC Class I 특이적억제수용체에는사람의 killer cell immunoglobulin-like receptor (KIR) 나생쥐의 lectin-like Ly49 수용체, 공통적인 lectin-like CD94/NKG2A 수용체등이있다. 최근에는표적세포의 MHC Class I 뿐만아니라 non-mhc 분자들을인식하는다양한억제수용체도발견되어그역할이규명중에있다 [26]. 대표적으로사람의 NKR-P1A (LLT-1 인식 ), 생쥐의 NKR-P1B (Clr-b 인식 ) 등이있다. 4. 자연살해세포의활성화기전자연살해세포의활성은이들세포에존재하는다양한활성화및억제수용체의신호전달균형에의해조절된다는것이알려져있다. 정상세포의경우이들세포에존재하는 MHC Class I 등이자연살해세포의억제수용체에의해인식되어자연살해세포의활성을억제하므로자연살해세포의공격을받지않는다. 그러나암세포나감염된세포의경우 MHC Class I의감소또는활성화수용체에대한 ligand 증가를통해자연살해세포를활성화시켜이들세포를제거한다고알려져있다. 자연살해세포의활성조절기전은초창기자연살해세포의억제수용체가표적세포의 MHC Class I을인식하는지여부에따라결정된다는 missing-self model 이주류를이루었다. 이모델에서는자연살해세포의 KIR이나 CD94/NKG2A 같은억제수용체가정상세포표면의 MHC Class I을인식하여자연살해세포의활성을억제하나암세포의경우억제수용체에대한 MHC Class I이충분치않아자연살해세포의활성이유도된다는것이다. 그러나항암활성에중요한 NKG2D, 2B4, DNAM-1, NCRs 등과같은다양한활성화수용체의발견을통해자연살해세포의활성은표적세포에결합한다양한활성화및억제수용체에서유 도된전체신호전달균형에의해결정된다는것이알려지게되었다 (dynamic equilibrium model)[27]. 이는자연살해세포활성화에활성 / 억제를결정짓는특정한계점이존재한다는것을의미하며아직까지이것이어떻게결정되는지는모호한상황이다 [28]. 최근의연구를통해많은활성화및억제수용체에서유도된신호가공통적으로 guanine nucleotide exchange factor (GEF) 인 Vav1 을조절한다는것이알려지고있다 [29,30]. 즉, 다양한활성화수용체는 Vav1 의인산화 (phosphorylation) 를유도하며반대로 inhibitory 수용체의경우 Vav1 의탈인산화 (dephosphorylation) 를유도하여자연살해세포의활성을조절하게된다. 그러나 ADCC를유도하는 CD16 의경우 Vav1 대신에 Vav2 와 Vav3 의인산화를유도한다고알려져있어활성화수용체에따라서로다른활성조절기전이존재할가능성이크다 [31]. 자연살해세포에는 B세포의 BCR, T세포의 T cell receptor (TCR) 같은 dominant 수용체가존재하지않기때문에다른면역세포와구별되는활성화기전이존재할것으로예측된다. 따라서항암활성에중요한특정수용체조합 (NKG2D, 2B4, DNAM-1 등 ) 을통해자연살해세포활성화기전을연구하는것은자연살해세포활성화이해의좋은모델이될수있으며이에대한연구가활발히진행되고있다 [29,32,33]. 5. 자연살해세포를이용한항암면역치료연구동향현재자연살해세포를이용한항암면역치료의경우자연살해세포억제수용체에초점이맞추어져있다 [11,34]. 즉자연살해세포활성을억제하는억제수용체의기능을차단함으로써자연살해세포의활성을증진시키고자하는것이다. 이를위해수혜자의 major histocompatibility complex (MHC) 와일치하지않는기증자의동종자연살해세포 (allogeneic NK cell) 를사용하거나억제수용체의기능을항체로써차단하는방법이주로사용되고있다. 1) 동종자연살해세포동종자연살해세포는기증자와수혜자의 MHC Class I 유전형이다르기때문에기증자자연살해세포의억제수용체 (KIR 등 ) 가수혜자 MHC Class I을인식하지못함으로써활성억제를받지않는다. 따라서동종자연살해세포의경우암세포에여전히존재할수있는 MHC Class I에의한활성억제에자유로울수있어그렇지못한환자자신의자연살해세포보다좀더효과적인항암활성을나타낼것으로예상할수있다. 실제로동종자연살해세포가항암치료에많은장점을가진다는것은처음혈액암환자치료에동종조혈줄기세포이식 (hematopoietic stem cell transplantation, HSCT) 가효과적이라는사실로부터알려지게되었다 [11,34]. 추가적인연구를통해이러한동종조혈줄기세포이식에서이식편대백혈병 (graftversus-leukemia, GVL) 반응의많은부분이자연살해세포에의한것임이알려지게되었다. 이에근거하여실제로건강한기증자의순 61

4 HMR Hun Sik Kim Natural Killer Cell and Cancer Immunotherapy 수분리된동종자연살해세포를체외에서대량으로배양하고활성화시켜암환자에투여하는많은시도가이루어지고있으며급성골수성백혈병 (acute myeloid leukemia, AML), 다발성골수종 (multiple myeloma, MM) 등에서효과적인항암활성을나타내었다. 하지만 MHC Class I이완전히불일치하는동종조혈줄기세포이식의경우환자에따라기대했던항암활성이나타나지않는경우가많고더불어 conditioning regimen 에포함된면역억제제에의한감염등심각한부작용들이보고되었다. 더욱이자연살해세포의경우최근연구들을통해자연살해세포의분화시충분한항암활성획득에억제수용체와표적세포 MHC Class I의상호작용 ( education 혹은 licensing 과정 ) 이필요하다는것이알려지게되었다 [35,36]. 따라서충분한항암활성을갖는성숙한자연살해세포를얻기위해서는기증자와수혜자의 MHC Class I이어느정도일치해야할것으로예상되고있다. 따라서이러한영향으로현재여러 MHC Class I 중하나가일치하는반일치 (haploidentical) 조혈줄기세포이식과자연살해세포를혈액암치료에많이시도하고있으며그에따른임상적예후가상대적으로뛰어나다는사실이확인되고있다 [34,37,38]. 또한동종면역세포를세포치료제로사용할경우수혜자자신의세포를공격하는이식편대숙주병 (graft-versus-host disease, GVHD) 등의부작용이필연적으로발생하는데반해동종자연살해세포의경우그러한문제점이거의보고되지않았다. 이는암세포와달리정상세포는자연살해세포활성화수용체에대한 ligand를거의발현하지않아자연살해세포활성화를유도하지않는것으로이해되고있다. 현재동종자연살해세포를혈액암외에다른고형암들에도세포치료제로사용하고자하는연구들이활발히시도되고있다. 2) 자연살해세포억제수용체특이적항체동종자연살해세포이식에의한치료법의경우많은장점에도불구하고아직까지임상적예후가나쁜환자들에게제한적으로시술되고있다. 더욱이이식에적합한기증자를찾는것과 conditioning regimen 에의한많은부작용등이아직까지큰문제점으로남아있다. 따라서이러한제약들을극복하고환자자신의자연살해세포로도안전하면서도비슷한효과를얻을수있는대안으로개발된것이자연살해세포억제수용체에특이적인인간화항체이다. 대표적으로 1-7F9 로불리는단일클론의인간화항체가개발되었는데이는다양한 KIR 억제수용체중 MHC Class I C형의대립형질 (alleles) 에결합하는모든 KIR2DL1,2,3 수용체들을차단한다 [39]. 따라서이인간화항체를환자에투여하게되면암세포에남아있는 HLA-C 대립형질을모두차단하여동종자연살해세포와비슷한효과를예측할수있다. 많은 AML, MM 세포의경우 MHC Class I을발현하고있어환자자신의자연살해세포의경우효과적인항암활성을기대할수없는경우가많다. 따라서 1-7F9 같은억 제수용체차단항체는상기의혈액암에서 MHC Class I에의한환자자신의자연살해세포활성억제를차단할수있으며실제로동물모델과전임상에서유망한결과를보여주었다 [39]. 3) 면역제제및약물학적제제동종자연살해세포이식에의한또하나의문제는이식된자연살해세포가수혜자에서오랫동안지속되지않는다는점이다. 이를극복하기위해이식후에자연살해세포증식을유도할수있는시토카인 IL-2를주기적으로넣어주는방법이시도되었다. 그러나 IL-2는자연살해세포외에도항암면역반응을억제하는조절 T세포 (Treg) 를증폭할수있기때문에큰문제점이될수있다 [34,40]. 따라서이를극복하기위해자연살해세포에선택적으로작용하여증식및활성화를유도할수있는 IL-15 이대안으로시도되고있다. 또하나자연살해세포억제수용체가비록자연살해세포활성화및정상세포와암세포를구분하는데핵심적으로작용하나언급한바와같이자연살해세포활성화에는활성화수용체에의한활성화신호전달이필수적이다. 다양한고형암및급성림프구성백혈병 (acute lymphoblastic leukemia, ALL) 의경우자연살해세포활성화수용체에대한 ligand가불충분하여자연살해세포활성을효과적으로유도하지못함이보고되고있다. 따라서암세포에서활성화수용체에대한 ligand 발현을증진시키거나자연살해세포자체의활성을증진시킬수있는방법들이모색되고있다 [34]. 이러한노력의결과로몇몇항암제 (5-FU, Ara-C, cisplatin) 의경우고유의항암활성과별개로암세포에서자연살해세포활성화수용체 (NKG2D 등 ) 에대한 ligand 발현을증진시킬수있음이보고되고있다. 최근다발성골수종등의치료에사용되고있는 bortezomib, lenalidomide (Revlimid) 의경우도암세포에서이러한 ligand들을발현시킬수있음이보고되었다. 하지만이러한항암제의경우경우에따라자연살해세포의활성을직접적으로억제할수있음도보고되어어떻게효과적으로자연살해세포기반의항암면역치료에활용될수있을지추가적인연구가필요한상황이다. 결론현재자연살해세포를이용하여다양한암을치료하기위한연구가전세계적으로활발하게진행되고있으며사람을대상으로한임상연구또한큰가능성을보여주고있다. 그러나이러한중요성에도불구하고자연살해세포의활성화기전이명확하지않아이를새로운치료제로개발하는데있어큰걸림돌이되고있다. 언급한바와같이자연살해세포활성화의가장큰특징은다양한활성화및억제수용체의특정조합을통해그활성이유도된다는것이다. 다른면역세포와구별되는이런차이점때문에아직까지다양한수용체로부터유도된활성화신호가어떻게통합되어자연살해세 62

5 김헌식 자연살해세포와항암면역치료 HMR 포활성을조절하는지모호한상황이다. 따라서기존의자연살해 세포를이용한항암치료는 IL-2 같은시토카인으로자연살해세포 를배양하여증진된항암활성을갖는 lymphokine activated killer (LAK) 세포를만들거나자연살해세포의활성을억제하는억제수 용체의활성을차단하기위해동종자연살해세포또는항체등으 로억제수용체를차단하는것이대세였다. 그러나이들방법은암 종류에따라효과가없거나개인별치료효과의차이및지속성등 여러문제점이나타나고있다. 따라서자연살해세포를이용한항 암면역치료법개발은자연살해세포의억제수용체뿐만아니라활 성화수용체, 암세포에서자연살해세포수용체 ligand 의발현조절 등다각도에서접근할필요가있다. 특히아직까지자연살해세포 활성화수용체의다양성및활성화신호의복잡성으로자연살해 세포활성화수용체를통한활성화기전에대한이해가미흡한편 이다. 따라서자연살해세포의정확한활성화기전을바탕으로자 연살해세포의면역활성을최적화한다면다양한암을보다효과적 으로치료할수있는방법이개발될수있을것으로기대된다. ACKNOWLEDGEMENTS This study was supported by a National Research Foundation of Korea Grant from the Korean Government (NRF ) and by the National R&D Program for Cancer Control ( ). REFERENCES 1. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008;9: Terme M, Ullrich E, Delahaye NF, Chaput N, Zitvogel L. Natural killer cell-directed therapies: moving from unexpected results to successful strategies. 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