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<!DOCTYPE html>
<html>
<head>
<title>Vähi immuunsus ja vähiravimid</title>
<meta charset="utf-8">
<meta name="description" content="Vähi immuunsus ja vähiravimid">
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</head>
<body style="opacity: 0">
<slides class="layout-widescreen">
<!-- LOGO SLIDE -->
<slide class="title-slide segue nobackground">
<hgroup class="auto-fadein">
<h1>Vähi immuunsus ja vähiravimid</h1>
<h2>Onkobioloogia</h2>
<p>Taavi Päll<br/>lektor, Tallinna Tehnikaülikool</p>
</hgroup>
<article></article>
</slide>
<!-- SLIDES -->
<slide class="" id="slide-1" style="background:;">
<article data-timings="">
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<!-- Presenter Notes -->
</slide>
<slide class="segue dark nobackground" id="slide-2" style="background:;">
<hgroup>
<h2>Immuunsus</h2>
</hgroup>
<article data-timings="">
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-3" style="background:;">
<hgroup>
<h2>Adaptiivne immuunsus</h2>
</hgroup>
<article data-timings="">
<p><img src="http://intranet.tdmu.edu.ua/data/kafedra/internal/patologanatom/classes_stud/en/med/lik/ptn/Pathomorphology/3/04_Pathomorph_immune_syst.files/image008.png" alt="adaptiivne immuunsus"></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-4" style="background:;">
<hgroup>
<h2>NK rakud ja makrofaagid</h2>
</hgroup>
<article data-timings="">
<p><img src="http://course1.winona.edu/kbates/Immunology/images/figure_09_41.jpg" alt="Ab-mediated bacteria engulfing"></p>
<p><img src="http://course1.winona.edu/kbates/Immunology/images/figure_09_43.jpg" alt="Ab-mediated target cell killing by NK cell"></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-5" style="background:;">
<hgroup>
<h2>T rakud</h2>
</hgroup>
<article data-timings="">
<ul>
<li>Helper T rakud (Th) on CD4+ ja vahendavad Tc ja B rakkude aktivatsiooni.</li>
<li>Tsütotoksilised T rakud (Tc) on CD8+ ja vahendavad patogeenide ja nakatunud rakkude eemaldamist.</li>
<li>Regulatoorsed T rakud (CD4+CD25+) supresseerivad Th ja Tc rakke, kontrollivad autoimmuunsust.</li>
</ul>
<p><img src="https://ka-perseus-images.s3.amazonaws.com/95c73f88aa68932b0637224f6670208006c5e079.svg" alt="T cell types"></p>
<p><footer class="source">Pilt: <a href="https://www.khanacademy.org/test-prep/mcat/organ-systems/the-immune-system/a/adaptive-immunity">khanacademy.org</a>
</footer></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-6" style="background:;">
<hgroup>
<h2>Koesobivusantigeenid</h2>
</hgroup>
<article data-timings="">
<div style='float:left;width:48%;' class='centered'>
<p><strong>a</strong>) MHC klass I molekulid presenteerivad enda antigeene.
<strong>b</strong>) Rakud millel MHC I puudub või<br>
<strong>c</strong>) rakud mis ei presenteeri enda antigeeni lüüsitakse tsütotoksiliste rakkude poolt.</p>
<p><img src="https://cdn.rcsb.org/pdb101/motm/images/1hsa-1dlh.gif" style="width:340px"/></p>
<p>Vasakul, MHC I; paremal, MHC II. Joonis: <a href="http://pdb101.rcsb.org/motm/62">PDB101</a>.</p>
</div>
<div style='float:right;width:48%;'>
<p><img src="http://www.nature.com/nri/journal/v5/n5/images/nri1603-f1.jpg" alt="MHC klass I"></p>
</div>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-7" style="background:;">
<hgroup>
<h2>Antikehad</h2>
</hgroup>
<article data-timings="">
<ul>
<li>Fc retseptoreid ekspresseerivad rakud - NK rakud ja makrofaagid seovad antikehadega kaetud raku ja tapavad selle</li>
<li>komplement seostub rakule seostunud antikehadele ja tapab raku muutes selle membraani poorseks </li>
</ul>
<p><img src="assets/img/ab-mediated-killing.png" alt="ab-mediated-killing"></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-8" style="background:;">
<hgroup>
<h2>Tsütotoksilised T rakud</h2>
</hgroup>
<article data-timings="">
<p><img src="http://www.nature.com/nri/journal/v10/n8/images/nri2803-f2.jpg" style="height:300px"/></p>
<p><img src="http://faculty.southwest.tn.edu/rburkett/A&P2%20L44.jpg" style="height:250px"/></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-9" style="background:;">
<hgroup>
<h2>Regulatoorsed T rakud</h2>
</hgroup>
<article data-timings="">
<p><img src="http://www.nature.com/nri/journal/v11/n2/images/nri2916-f1.jpg" alt="Treg"></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="segue dark nobackground" id="slide-10" style="background:;">
<hgroup>
<h2>Vähi immuunsus ja immuunoteraapia</h2>
</hgroup>
<article data-timings="">
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-11" style="background:;">
<hgroup>
<h2>Vähi immuunoseire</h2>
</hgroup>
<article data-timings="">
<h1><em>Cancer immunosurveillance</em></h1>
<ul>
<li>1909. aastal oletas saksa-juudi päritolu arst <a href="http://en.wikipedia.org/wiki/Paul_Ehrlich">Paul Ehrlich</a> (1854-1915) et immuunsüsteem hoiab ära kartsinoomide tekke, mis vastasel juhul oleksid palju sagedasemad.</li>
<li>Vähi immuunoseire hüpotees oletas, et tüümusest pärit rakud monitoorivad keha kudedes ka uusi transformeerunud rakke <a href="http://www.ncbi.nlm.nih.gov/pubmed/4921480">Frank Macfarlane Burnet, 1970</a>.</li>
</ul>
<div style='float:left;width:48%;' class='centered'>
<p><img src="https://upload.wikimedia.org/wikipedia/commons/thumb/0/05/Paul_Ehrlich_1915.jpg/800px-Paul_Ehrlich_1915.jpg" style="height:200px"/></p>
<p><footer class="source">Pilt: wikipedia.
</footer></p>
</div>
<div style='float:right;width:48%;'>
<p><img src="http://upload.wikimedia.org/wikipedia/commons/thumb/5/5b/Frank_Macfarlane_Burnet.jpg/800px-Frank_Macfarlane_Burnet.jpg" style="height:200px"/></p>
</div>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-12" style="background:;">
<hgroup>
<h2>Vähirakkudega ei saa nakatada</h2>
</hgroup>
<article data-timings="">
<p>Vähirakud saavad moodustada uue vähi ainult geneetiliselt identses backgroundis, vastasel juhul nad hävitatakse immuunsüsteemi poolt </p>
<p><img src="http://4.bp.blogspot.com/-WHsdxWMPQtw/VUvT0BwFECI/AAAAAAAABXI/s3bBD7j9DM8/s1600/PicsArt_1431032190753.jpg" alt="süngenne host"></p>
<p><footer class="source">Pilt:<a href="http://www.nature.com/nature/journal/v521/n7550/full/nature14424.html">"Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity"</a>
</footer></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-13" style="background:;">
<hgroup>
<h2>Vähi immuunokujundamine</h2>
</hgroup>
<article data-timings="">
<h1><em>Cancer immunoediting</em></h1>
<ul>
<li>Alternatiivseks hüpoteesiks vähirakkude ja immuunsüsteemi interaktsioonide kirjeldamiseks on <strong>vähi immuunokujundamise</strong>.</li>
<li>Vähi <strong>täielik elimineerimine immuunsüsteemi poolt</strong> on immuunokujundamise üks stsenaarium. </li>
<li>Teine stsenaarium on <strong>immuunsüsteemi poolt kujundatud vähirakkude</strong> repertuaari esiletõus. </li>
<li>Immuunsüsteemiga kohandunud vähirakud on kas
<ul>
<li><strong>vähem immuunogeneesed</strong>,</li>
<li>suurenenud <strong>võimega inhibeerida vähivastast immuunvastust</strong>.</li>
</ul></li>
</ul>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-14" style="background:;">
<hgroup>
<h2>Vähi immuunoseire/-kujundamine</h2>
</hgroup>
<article data-timings="">
<h1>Vähi immuunoseire või -kujundamise toimimisele inimeses viitavad</h1>
<ul>
<li>Kõrgem vähi intsidents immuunosupressiivset ravi saavatel organi transplantatsiooni läbinud patsientidel.</li>
<li>Vähipatsientidel tekib oma vähi vastu immuunvastus.</li>
<li>Vähisiseste tsütotoksiliste (CD8+) ja immuun-protektiivsete regulatoorsete (CD25+Foxp3+) T rakkude lokalisatsioon.</li>
</ul>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-15" style="background:;">
<hgroup>
<h2>Kõrgem vähi intsidents immuunosupressiivse ravi puhul</h2>
</hgroup>
<article data-timings="">
<ul>
<li>Organi transplantatsiooni läbinud patsiendid saavad tugevat immuunosupressiivset ravi.</li>
</ul>
<div style='float:left;width:48%;' class='centered'>
<p><img src="assets/fig/organ-1.png" alt="plot of chunk organ"></p>
</div>
<div style='float:right;width:48%;'>
<p>Nahavähi populatsioon-standardiseeritud intsidents organi transplantatsiooni patsientidel (Norra ja Holland).</p>
<table><thead>
<tr>
<th>Nahavähk</th>
<th>intsidentsi kasv</th>
</tr>
</thead><tbody>
<tr>
<td>SCC</td>
<td>65-korda</td>
</tr>
<tr>
<td>huule SCC</td>
<td>20-korda</td>
</tr>
<tr>
<td>BCC</td>
<td>10-korda</td>
</tr>
<tr>
<td>melanoom</td>
<td>3.4-korda</td>
</tr>
<tr>
<td>Kapoosi sarkoom</td>
<td>84-korda</td>
</tr>
</tbody></table>
<p><footer class="source">Graafik: Transplant Patient DataSource. United Network for Organ Sharing. Tabel:
<a href="http://www.ncbi.nlm.nih.gov/pubmed/2316011">Hartevelt et al., 1990.
</a>
<a href="http://www.ncbi.nlm.nih.gov/pubmed/10642700">Jensen et al., 2000.
</a>
Lisaks:
<a href="http://www.hudlaeknastodin.is/resources/Um-okkur/BS/Ca_Org_transpl.pdf">Lindelöf et al., 2000.
</a> ja
<a href="http://www.sciencedirect.com/science/article/pii/S0190962202000117">Berg & Otley, 2002.
</a>
</footer></p>
</div>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-16" style="background:;">
<hgroup>
<h1>Vähi intsidents organi transplantatsiooni patsientidel</h1>
</hgroup>
<article data-timings="">
<table><thead>
<tr>
<th align="left">Site of cancer</th>
<th align="right">No. cases observed</th>
<th align="right">No. cases expected</th>
<th align="right">Ratio obs/exp (adj)</th>
</tr>
</thead><tbody>
<tr>
<td align="left">non melanoma skin</td>
<td align="right">127</td>
<td align="right">5.1</td>
<td align="right">21.7</td>
</tr>
<tr>
<td align="left">thyroid other endocrine</td>
<td align="right">30</td>
<td align="right">2.1</td>
<td align="right">11.0</td>
</tr>
<tr>
<td align="left">mouth tongue lip</td>
<td align="right">22</td>
<td align="right">1.6</td>
<td align="right">10.0</td>
</tr>
<tr>
<td align="left">cervix vulva vagina</td>
<td align="right">39</td>
<td align="right">3.6</td>
<td align="right">9.4</td>
</tr>
<tr>
<td align="left">non-Hodgkins lymphoma</td>
<td align="right">25</td>
<td align="right">2.4</td>
<td align="right">8.5</td>
</tr>
<tr>
<td align="left">kidney ureter</td>
<td align="right">32</td>
<td align="right">3.5</td>
<td align="right">8.0</td>
</tr>
<tr>
<td align="left">bladder</td>
<td align="right">26</td>
<td align="right">4.7</td>
<td align="right">5.2</td>
</tr>
<tr>
<td align="left">colorectal</td>
<td align="right">38</td>
<td align="right">10.5</td>
<td align="right">3.6</td>
</tr>
<tr>
<td align="left">lung</td>
<td align="right">30</td>
<td align="right">12.5</td>
<td align="right">2.5</td>
</tr>
<tr>
<td align="left">brain</td>
<td align="right">10</td>
<td align="right">4.1</td>
<td align="right">2.6</td>
</tr>
<tr>
<td align="left">prostate</td>
<td align="right">11</td>
<td align="right">5.2</td>
<td align="right">2.3</td>
</tr>
<tr>
<td align="left">melanoma</td>
<td align="right">7</td>
<td align="right">4.1</td>
<td align="right">2.0</td>
</tr>
<tr>
<td align="left">breast</td>
<td align="right">15</td>
<td align="right">13.6</td>
<td align="right">1.2</td>
</tr>
</tbody></table>
<p><footer class="source">Tabel: <a href="http://www.nature.com/nature/journal/v411/n6835/full/411390a0.html">Peto, J (2001)</a>. Cancer epidemiology in the last century and the next decade. Nature, 411, 6835:390-5.
<a href="http://onlinelibrary.wiley.com/doi/10.1002/ijc.2910600209/abstract">Birkeland, et al. (1995)</a>. Cancer risk after renal transplantation in the Nordic countries, 1964-1986. Int. J. Cancer, 60, 2:183-9. ADJustment by empirical Bayesian shrinkage towards a Beta prior.
</footer></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-17" style="background:;">
<hgroup>
<h2>Immuunpuudulikel hiirtel tekib rohkem kasvajaid</h2>
</hgroup>
<article data-timings="">
<div style='float:left;width:48%;' class='centered'>
<ul>
<li>Metsik tüüpi või RAG2 -/- hiirtele süstiti naha alla 100 $\mu$g kartsinogeenset 3-metüülkolantreeni (<em>methylcholanthrene</em>, MCA) ja jälgiti vähiteket.</li>
<li>160 päeva pärast oli 9/15 RAG2-/- hiirel moodustunud MCA-indutseeritud vähid, samas oli sama moodi indutseeritud vähk tekkinud ainult 2/15 wild-type hiirel.</li>
<li>RAG2-/- hiirtel puuduvad T-, B- ja NK-T rakud.</li>
</ul>
<p><footer class="source">Pilt: IFNbig gamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.
<a href="http://www.nature.com/nature/journal/v410/n6832/full/4101107a0.html">
Shankaran et al., 2001.
</a>
</footer></p>
</div>
<div style='float:right;width:48%;'>
<p><img src="http://www.nature.com/nature/journal/v410/n6832/images/4101107ab.2.jpg" alt=""></p>
</div>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-18" style="background:;">
<hgroup>
<h1>Vähid mis tekivad hiires kellel puuduvad lümfotsüüdid on immunogeensemad</h1>
</hgroup>
<article data-timings="">
<div style='float:left;width:48%;' class='centered'>
<ul>
<li>Immuunopuudulikele RAG2-/- hiirtele või metsik tüüpi hiirtele transplanteeriti naha alla 100'000 vähirakku, mis pärinesid RAG2-/- või wt hiirtest eraldatud MCA-indutseeritud tuumoritest.</li>
<li>Süngeensetest wt hiirtest pärit 17 erineva vähi rakud moodustasid tuumoreid 100% (17/17) wt hiirtes.</li>
<li>RAG2-/- hiirtest pärit vähirakud (20 erinevast tuumorist) moodustasid tuumoreid ainult 40% juhtudest (8/20) kui neid transplanteeriti sama geneetilise tagapõhjaga imuunkompetentsetele hiirtele.</li>
</ul>
<p><footer class="source">Pilt: IFNbig gamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.
<a href="http://www.nature.com/nature/journal/v410/n6832/full/4101107a0.html">
Shankaran et al., 2001.
</a>
</footer></p>
</div>
<div style='float:right;width:48%;'>
<p><img src="http://www.nature.com/nature/journal/v410/n6832/images/4101107ac.2.jpg" alt=""></p>
</div>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-19" style="background:;">
<hgroup>
<h2>Kas rakulised onkogeenid on immunogeensed?</h2>
</hgroup>
<article data-timings="">
<ul>
<li>Mutantsete vähi ja normaalsete valkude erinevused on väikesed: RAS, TP53, BCR-ABL.</li>
<li>Trioosfosfaat isomeraas (glükolüüsi rada) on mitmetes vähkides immunogeenne.</li>
<li>Mutantse RAS valgu struktuur ei ole muutunud (nt. KRASG12V vs. wt KRAS), madal immunogeensus ja lisaks on onkogeensed RAS valgud madalalt ekspresseeritud.</li>
</ul>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-20" style="background:;">
<hgroup>
<h2>Vähis võib tekkida immuunvastus kõrgelt ekspresseeritud valkude vastu</h2>
</hgroup>
<article data-timings="">
<ul>
<li>hTERT on üleekspresseeritud 70-80% vähkides. Maksakartsinoomi patsientidel hTERT-vastased antikehad veres. Nende antikehade roll progressioonis ebaselge.</li>
<li>HER2/neu positiivsed rinnakartsinoomid, seal 10-20x üleekspressioon (trastuzumab).</li>
<li>GD3 gangliosiid (siaalhapet sisaldav glükosfingolipiid) on mitmetes vähkides (melanoon sh.) üle ekspresseeritud.</li>
</ul>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-21" style="background:;">
<hgroup>
<h2>Vähi antigeenid</h2>
</hgroup>
<article data-timings="">
<ol>
<li>TSTA - <em>tumor specific transplantation antigens (TA)</em> strukturaalselt uudsed, kindla vähi või vähitüübiga seotud antigeenid mida ei esine normaalsetes kudedes.</li>
<li>TATA/TAA - <em>tumor associated TA</em> -- vähis ekspresseeritud normaalsed valgud mille suhtes pole mingil põhjusel täielikku tolerantsust tekkinud.</li>
</ol>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-22" style="background:;">
<article data-timings="">
<table><thead>
<tr>
<th>Vähitüüp</th>
<th>Valk</th>
<th>Antigenne peptiid</th>
</tr>
</thead><tbody>
<tr>
<td>melanoom, suuõõne kartsinoom, maksa kartsinoom, mitte-väikserakuline kopsuvähk</td>
<td>MAGE</td>
<td>EADPTGHSY, SAYGEPRKL</td>
</tr>
<tr>
<td>melanoom</td>
<td>türosinaas</td>
<td>MLLAVLYCL, YMNGTMSQV</td>
</tr>
<tr>
<td>käärsoole kartsinoom</td>
<td>kartsino-embrüonaalne antigeen (CEA)</td>
<td>YLSGANLNL</td>
</tr>
<tr>
<td>rinna- ja munasarja kartsinoomid</td>
<td>HER2/neu</td>
<td>KIFGSLAFL</td>
</tr>
<tr>
<td>pea-kaela kartsinoom</td>
<td>kaspaas 8</td>
<td>FPSDWCYF</td>
</tr>
<tr>
<td>krooniline müelogeenne leukeemia (CML)</td>
<td>BCR-ABL</td>
<td>ATGFKQSSKALQRPVAS</td>
</tr>
<tr>
<td>eesnäärme kartsinoom</td>
<td>eesnäärme spetsiifiline antigeen (PSA)</td>
<td>FLTPKKKLQCV, VISNDVCAQV</td>
</tr>
</tbody></table>
<p><footer class="source">Tabel: R.A. Goldsby et al., Immunology, 5th ed. New York: Freeman 2002; B.J. Van den Eynde and P. van der Bruggen, Curr Opin. Immunol. 9:684-693, 1997. Adapteeritud: The Biology of Cancer, 2007.
</footer></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-23" style="background:;">
<hgroup>
<h2>Keemiliselt indutseeritud fibrosarkoomi antigeenide spetsiifilisus</h2>
</hgroup>
<article data-timings="">
<ul>
<li>BALB/c hiiri immuniseeriti 3-MC-indutseeritud Meth A fibrosarkoomi lüsaadiga</li>
<li>Immuniseeritud hiirtest eraldati antigeeni presenteerivad 24D3 lümfotsüüdid</li>
<li>Ainult Meth A lüsaat indutseeris neid lümfotsüüte jagunema (A, vasakul)</li>
<li>24D3 lümfotsüütidega transplanteeritud hiirtes kasvab küll teine samasugune fibrosarkoom (CMS5, kõige parempoolne pilt) aga mitte Meth A (keskel).</li>
</ul>
<p><img src="assets/fig/metha-1.png" alt="plot of chunk metha"></p>
<p><footer class="source">T. Matsutake and P.K. Srivastava, 2001. PNAS98:3992-3997. The immunoprotective MHC II epitope of a chemically induced tumor harbors a unique mutation in a ribosomal protein. doi: 10.1073/pnas.071523398
</footer></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-24" style="background:;">
<hgroup>
<h1>Inimese GI vähi mutatsioonide immunogeensus</h1>
</hgroup>
<article data-timings="">
<table><thead>
<tr>
<th align="left">ID</th>
<th align="left">Age/sex</th>
<th align="left">Tumor</th>
<th align="left">Mutated prot</th>
<th align="left">Aa change</th>
<th align="left">T cell type</th>
<th align="left">% in tumor</th>
</tr>
</thead><tbody>
<tr>
<td align="left">3737*</td>
<td align="left">45/F</td>
<td align="left">Bile duct</td>
<td align="left">ERBB2IP</td>
<td align="left">E805G</td>
<td align="left">CD4</td>
<td align="left">0.009</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">E805G</td>
<td align="left">CD4</td>
<td align="left">0.375</td>
</tr>
<tr>
<td align="left">3812</td>
<td align="left">44/M</td>
<td align="left">Bile duct</td>
<td align="left">—</td>
<td align="left">—</td>
<td align="left">—</td>
<td align="left">—</td>
</tr>
<tr>
<td align="left">3942</td>
<td align="left">46/F</td>
<td align="left">Rectal</td>
<td align="left">NUP98</td>
<td align="left">A359D</td>
<td align="left">CD8</td>
<td align="left">0.67</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">KARS</td>
<td align="left">D356</td>
<td align="left">CD8</td>
<td align="left">0.020</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">GPD2</td>
<td align="left">E426K</td>
<td align="left">CD4</td>
<td align="left">0.037</td>
</tr>
<tr>
<td align="left">3948</td>
<td align="left">48/M</td>
<td align="left">Esophageal</td>
<td align="left">PLEC</td>
<td align="left">E1179K</td>
<td align="left">CD4</td>
<td align="left">NE</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">XPO7</td>
<td align="left">P274S</td>
<td align="left">CD4</td>
<td align="left">NE</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">AKAP2</td>
<td align="left">Q418K</td>
<td align="left">CD4</td>
<td align="left">NE</td>
</tr>
<tr>
<td align="left">3971</td>
<td align="left">49/M</td>
<td align="left">Colon</td>
<td align="left">CASP8</td>
<td align="left">F67V</td>
<td align="left">CD8</td>
<td align="left">1.25</td>
</tr>
<tr>
<td align="left">3978</td>
<td align="left">46/F</td>
<td align="left">Bile duct</td>
<td align="left">ITGB4</td>
<td align="left">S1002I</td>
<td align="left">CD4</td>
<td align="left">NE</td>
</tr>
<tr>
<td align="left">3995</td>
<td align="left">50/M</td>
<td align="left">Colon</td>
<td align="left">TUBGCP2</td>
<td align="left">P293L</td>
<td align="left">CD8</td>
<td align="left">0.023</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">RNF213</td>
<td align="left">N1702S</td>
<td align="left">CD8</td>
<td align="left">0.60</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">KRAS</td>
<td align="left">G12D</td>
<td align="left">CD8</td>
<td align="left">0.055</td>
</tr>
<tr>
<td align="left">4007</td>
<td align="left">52/M</td>
<td align="left">Colon</td>
<td align="left">SKIV2L</td>
<td align="left">R653H</td>
<td align="left">CD8</td>
<td align="left">0.090</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">R653H</td>
<td align="left">CD8</td>
<td align="left">0.014</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">H3F3B</td>
<td align="left">A48T</td>
<td align="left">CD8</td>
<td align="left">1.19</td>
</tr>
<tr>
<td align="left">4032</td>
<td align="left">46/M</td>
<td align="left">Colon</td>
<td align="left">API5</td>
<td align="left">R243Q</td>
<td align="left">CD8</td>
<td align="left">0.083</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">R243Q</td>
<td align="left">CD8</td>
<td align="left">0.059</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">RNF10</td>
<td align="left">E572K</td>
<td align="left">CD8</td>
<td align="left">0.030</td>
</tr>
<tr>
<td align="left"></td>
<td align="left"></td>
<td align="left"></td>
<td align="left">PHLPP1</td>
<td align="left">G566E</td>
<td align="left">CD8</td>
<td align="left">0.081</td>
</tr>
<tr>
<td align="left">4069</td>
<td align="left">57/M</td>
<td align="left">Pancreatic</td>
<td align="left">ZFYVE27</td>
<td align="left">R6H</td>
<td align="left">CD8</td>
<td align="left">0.088</td>
</tr>
</tbody></table>
<p><footer class="source">Tabel: Mutation-reactive T cells in metastatic GI cancers <a href="http://www.sciencemag.org/content/350/6266/1387/T1.expansion.html">Tran, et al., (2015)</a> Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 11 December 2015: Vol. 350 no. 6266 pp. 1387-1390
</footer></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-25" style="background:;">
<hgroup>
<h2>Immuunrakud kasvaja mikrokeskonnas</h2>
</hgroup>
<article data-timings="">
<div style='float:left;width:48%;' class='centered'>
<p><img src="http://www.nature.com/mt/journal/v18/n2/images/mt2009228f2.gif" style="width:460px;"></p>
<p><footer class="source">Pilt <a href="http://www.nature.com">www.nature.com</a>
</footer></p>
</div>
<div style='float:right;width:48%;'>
<ul>
<li>T lümfotsüüdid</li>
<li>B lümfotsüüdid</li>
<li>NK ja NKT rakud</li>
<li>makrofaagid</li>
<li>müeloidset päritolu suppressor-rakud</li>
<li>dendriitrakud</li>
<li>neutrofiilid</li>
</ul>
</div>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-26" style="background:;">
<hgroup>
<h2>NKG2D ja ligandid</h2>
</hgroup>
<article data-timings="">
<h1>NKG2D on aktivatsiooniretseptoriks NK rakkudel -- aktiveerivad <em>killer immunoglobulin-like receptor</em> (KIR) molekulid (NKR-P1, CD94/NKG2(A/B))</h1>
<div style='float:left;width:48%;' class='centered'>
<p><img src="http://www.nature.com/nri/journal/v7/n9/images/nri2144-f1.jpg" alt="nkg2d"></p>
</div>
<div style='float:right;width:48%;'>
<ul>
<li>NKG2D ekspr. vastusena stressile või DNA kahjustustele, samuti konstitutiivselt vähirakkudel.</li>
<li>NKG2D ligandid on MICA/B ja RAE valgud</li>
<li>MICA seostumine NKG2D-le aktiveerib NK rakud</li>
<li>RAE üleekspressioon hiires muudab need loomad vastuvõtlikumaks kartsinogeneesile.</li>
<li>Inimese kartsinoomid ja melanoomid üleekspresseerivad lahustuvat MICA ligandi (tekib proteolüütilise lõikamise teel, <em>shedding</em>)</li>
</ul>
<p><footer class="source">Pilt: Nature Immunology.
</footer></p>
</div>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-27" style="background:;">
<hgroup>
<h2>Inhibeerivad KIR valgud</h2>
</hgroup>
<article data-timings="">
<h1>NK vastust vähile reguleerib signaalide tasakaal</h1>
<ul>
<li>Inhibeeriv KIR blokeerib MHC-I molekuliga interakteerudes NK rakkude vastuse.</li>
<li>Rakud millel puuduvad MHC-I molekulid vallandavad NK-vastuse ja tapetakse.</li>
<li>Osadel kasvajatüüpidel on MHC-I puudumine seotud parema vastusega.</li>
</ul>
<p><img src="http://www.frontiersin.org/files/Articles/38940/fimmu-04-00076-HTML/image_m/fimmu-04-00076-g001.jpg" alt=""></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-28" style="background:;">
<hgroup>
<h2><em>Programmed death-1</em> vähi immunsupressioonis</h2>
</hgroup>
<article data-timings="">
<ul>
<li>Vähirakud suruvad adaptiivse immuunvastuse alla ka selleläbi, et reguleerivad ülesse <strong>PD-1 ligandi (PD-L1)</strong>.</li>
<li>PD-1L on vähirakkudel konstitutiivselt ekspresseeritud.</li>
<li>PD-L1 seostumine antigeen-spetsiifilistele CD8+ T rakkudel olevale PD-1 retseptorile surub alla nende T rakkude effektor funktsioonid (rakkude tapmine).</li>
<li>Sarnaselt immuunsupressiivselt toimib ka vähirakkudel jt. keharakkudel ekspresseeritav CTLA-4</li>
</ul>
<p><img src="http://www.nature.com/nbt/journal/v30/n8/images/nbt0812-729-I1.gif" alt=""></p>
<p><footer class="source">Pilt: Vähi checkpoint teraapia.
<a href="http://www.nature.com/news/antibody-alarm-call-rouses-immune-response-to-cancer-1.10784">
Hayden, 2012.
</a>
</footer></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="segue dark nobackground" id="slide-29" style="background:;">
<hgroup>
<h2>Vähiravimid</h2>
</hgroup>
<article data-timings="">
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-30" style="background:;">
<hgroup>
<h2>Vähitrendid 20. sajandil</h2>
</hgroup>
<article data-timings="">
<p><img src="assets/fig/unnamed-chunk-1-1.png" alt="plot of chunk unnamed-chunk-1"></p>
<p><footer class="source">Andmed: Long-Term Trends in Cancer Mortality in the United States, 1930 –1998. Wingo et al.,
<a href="http://onlinelibrary.wiley.com/doi/10.1002/cncr.11380/pdf">2003</a>.
</footer></p>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-31" style="background:;">
<hgroup>
<h2>Kaks peamist trendi vähisuremuses</h2>
</hgroup>
<article data-timings="">
<h1>Vähi suremus peegeldab ravi efektiivsust</h1>
<ul>
<li><strong>Suremus osadesse kasvajatüüpidesse on vähenenud</strong>. Tingituna näiteks mao- ja maksakasvajate puhul paremast toiduohutusest (<em>H. pylori</em>) ja emakakaela (ja soole-) kasvajate puhul sõeltestimistest.</li>
<li><strong>Mitmed põhilised kasvajatüübid on jäänud resistentseks</strong> enamuse kasutatavate ravimeetodite suhtes.</li>
<li>Enamus laialt kasutatavatest vähiravimitest on kasutusele võetud juba enne 1970-ndaid aastaid, mil puudus arusaam vähi molekulaarsetest alustest.</li>
</ul>
</article>
<!-- Presenter Notes -->
</slide>
<slide class="" id="slide-32" style="background:;">
<hgroup>
<h2>Esmased vähid ja 5 aasta suremus</h2>
</hgroup>
<article data-timings="">
<h1>Käärid vähi diagnoosimise ja eduka ravi vahel</h1>
<p><img src="assets/img/331_1540a_F1.jpg" alt="suremus"></p>
<p><footer class="source">Pilt: Cancer Research and the $90 Billion Metaphor. Eliot Marshall,
<a href="http://www.sciencemag.org/content/331/6024/1540.1.full">2011</a>.
</footer></p>