0 11 Stimulation stimulation NN 12 14 of of IN 15 19 CD40 cd40 NN 20 22 on on IN 23 34 immunogenic immunogenic JJ 35 40 human human JJ 41 50 malignant malignant JJ 51 60 melanomas melanoma NNS 61 69 augments augment VBZ 70 75 their their PRP$ 76 85 cytotoxic cytotoxic JJ 86 87 T t NN 88 107 lymphocyte-mediated lymphocyte-mediated JJ 108 113 lysis lysis NN 114 117 and and CC 118 125 induces induce VBZ 126 135 apoptosis apoptosis NN 135 136 . . . 138 142 Here here RB 142 143 , , , 144 146 we we PRP 147 153 report report VBP 154 157 the the DT 158 168 functional functional JJ 169 179 expression expression NN 180 182 of of IN 183 187 CD40 cd40 NN 188 190 on on IN 191 196 human human JJ 197 206 malignant malignant JJ 207 216 melanomas melanoma NNS 217 218 ( ( ( 218 221 MMs MM NNP 221 222 ) ) ) 222 223 . . . 224 234 Comparison comparison NN 235 237 of of IN 238 243 tumor tumor NN 244 252 specimen specimen NN 253 257 from from IN 258 260 MM MM NNP 261 270 precursor precursor NN 271 278 lesions lesion NNS 278 279 , , , 280 287 primary primary JJ 288 294 tumors tumor NNS 294 295 , , , 296 299 and and CC 300 310 metastases metastasis NNS 311 319 revealed reveal VBD 320 324 that that IN 325 329 CD40 CD40 NNP 330 337 surface surface NN 338 348 expression expression NN 349 351 is be VBZ 352 366 down-regulated down-regulate VBN 367 373 during during IN 374 379 tumor tumor NN 380 391 progression progression NN 391 392 . . . 393 397 CD40 CD40 NNP 398 408 expression expression NN 409 412 was be VBD 413 422 confirmed confirm VBN 423 425 in in IN 426 427 7 7 CD 428 433 human human JJ 434 436 MM MM NNP 437 441 cell cell NN 442 447 lines line NNS 448 459 established establish VBN 460 464 from from IN 465 476 immunogenic immunogenic JJ 477 484 primary primary JJ 485 491 tumors tumor NNS 492 494 or or CC 495 505 metastases metastasis NNS 505 506 , , , 507 514 whereas whereas IN 515 517 11 11 CD 518 522 cell cell NN 523 528 lines line NNS 529 540 established establish VBN 541 545 from from IN 546 554 advanced advance VBN 555 561 stages stage NNS 562 566 were be VBD 567 571 CD40 cd40 NN 572 580 negative negative JJ 580 581 . . . 582 586 CD40 CD40 NNP 587 597 expression expression NN 598 603 could could MD 604 606 be be VB 607 615 enhanced enhance VBN 616 618 in in IN 619 632 CD40-positive cd40-positive JJ 633 635 MM mm NN 636 638 by by IN 639 650 stimulation stimulation NN 651 655 with with IN 656 665 IFN-gamma IFN-gamma NNP 666 669 and and CC 670 675 tumor tumor NN 676 684 necrosis necrosis NN 685 697 factor-alpha factor-alpha NN 698 701 but but CC 702 705 not not RB 706 708 by by IN 709 720 interleukin interleukin NN 721 722 ( ( ( 722 731 IL)-1beta IL)-1beta NNP 732 734 or or CC 735 739 CD40 CD40 NNP 740 750 triggering triggering NN 750 751 . . . 752 756 CD40 CD40 NNP 757 765 ligation ligation NN 766 768 on on IN 769 771 MM MM NNP 772 774 by by IN 775 792 CD40L-transfected cd40l-transfected JJ 793 799 murine murine JJ 800 807 L-cells l-cell NNS 808 810 or or CC 811 813 by by IN 814 815 a a DT 816 823 soluble soluble JJ 824 829 CD40L CD40L NNP 830 836 fusion fusion NN 837 844 protein protein NN 845 857 up-regulated up-regulate VBD 858 863 their their PRP$ 864 874 expression expression NN 875 877 of of IN 878 891 intercellular intercellular JJ 892 900 adhesion adhesion NN 901 911 molecule-1 molecule-1 NN 912 915 and and CC 916 919 MHC MHC NNP 920 925 class class NN 926 927 I i CD 928 931 and and CC 932 937 class class NN 938 940 II ii CD 941 950 molecules molecule NNS 951 954 and and CC 955 960 their their PRP$ 961 970 secretion secretion NN 971 973 of of IN 974 978 IL-6 IL-6 NNP 978 979 , , , 980 984 IL-8 IL-8 NNP 984 985 , , , 986 991 tumor tumor NN 992 1000 necrosis necrosis NN 1001 1009 factor-a factor-a NN 1009 1010 , , , 1011 1014 and and CC 1015 1026 granulocyte granulocyte NN 1027 1037 macrophage macrophage NN 1038 1056 colony-stimulating colony-stimulating JJ 1057 1063 factor factor NN 1064 1067 and and CC 1068 1072 also also RB 1073 1080 induced induce VBD 1081 1082 a a DT 1083 1088 rapid rapid JJ 1089 1099 activation activation NN 1100 1102 of of IN 1103 1106 the the DT 1107 1120 transcription transcription NN 1121 1127 factor factor NN 1128 1135 nuclear nuclear JJ 1136 1142 factor factor NN 1143 1149 kappaB kappab NN 1149 1150 . . . 1151 1162 Furthermore furthermore RB 1162 1163 , , , 1164 1168 CD40 cd40 NN 1169 1177 ligation ligation NN 1178 1180 of of IN 1181 1182 a a DT 1183 1190 HLA-A2+ hla-a2+ JJ 1190 1191 , , , 1192 1205 MelanA/MART1+ melana/mart1+ JJ 1206 1208 MM MM NNP 1209 1213 cell cell NN 1214 1218 line line NN 1219 1227 enhanced enhance VBD 1228 1231 its its PRP$ 1232 1246 susceptibility susceptibility NN 1247 1249 to to TO 1250 1258 specific specific JJ 1259 1264 lysis lysis NN 1265 1267 by by IN 1268 1269 a a DT 1270 1287 HLA-A2-restricted hla-a2-restricted JJ 1287 1288 , , , 1289 1311 MelanA/MART-1-specific melana/mart-1-specific JJ 1312 1315 CTL CTL NNP 1316 1321 clone clone NN 1321 1322 . . . 1323 1330 Finally finally RB 1330 1331 , , , 1332 1336 CD40 CD40 NNP 1337 1345 ligation ligation NN 1346 1353 induced induce VBD 1354 1360 growth growth NN 1361 1371 inhibition inhibition NN 1372 1375 and and CC 1376 1385 apoptosis apoptosis NN 1386 1388 in in IN 1389 1391 MM MM NNP 1391 1392 . . . 1393 1398 These these DT 1399 1406 results result NNS 1407 1415 indicate indicate VBP 1416 1420 that that IN 1421 1431 CD40-CD40L cd40-cd40l NN 1432 1444 interactions interaction NNS 1445 1448 may may MD 1449 1453 play play VB 1454 1456 an an DT 1457 1466 important important JJ 1467 1471 role role NN 1472 1474 in in IN 1475 1485 augmenting augment VBG 1486 1495 antitumor antitumor JJ 1496 1504 immunity immunity NN 1505 1508 and and CC 1509 1517 inducing induce VBG 1518 1527 apoptosis apoptosis NN 1528 1530 in in IN 1531 1535 some some DT 1536 1549 CD40-positive cd40-positive JJ 1550 1561 immunogenic immunogenic JJ 1562 1567 human human JJ 1568 1571 MMs mm NNS 1571 1572 . . .