Two mechanisms for tumor evasion of preexisting cytotoxic T-cell responses: lessons from recurrent tumors.
Tumors evade host immunity at both the induction and effector phases Most studies have focused on tumor evasion at the induction phase, and, due in part to poor antitumor CTL responses to most tumors, the mechanism for evasion of CTL effector function is less clear. Here we have taken advantage of the strong CTL responses to a costimulator B7-1-transfected tumor to study the mechanism for tumor evasion of preexisting host immunity. We have investigated six independent recurrent tumors isolated from mice that were challenged with and had rejected B7-1-transfected J558 (J558-B7) tumors. Because the mice had developed strong antitumor CTL responses, these recurrent tumors must have evaded preexisting antitumor CTLs. Indeed, whereas the parental J558-B7 cell line is efficiently lysed by the ex vivo tumor-infiltrating lymphocytes, all of the recurrent tumors are resistant to such lysis. Interestingly, the recurrent tumors can be divided into two groups. The group 1 tumors have vastly reduced levels of cell surface MHC class I with a concurrent reduction in the expression of multiple genes devoted to MHC class I antigen presentation. In contrast, the group 2 tumors have lost the expression of costimulatory molecule B7-1 while retaining cell surface MHC class I and expression of all antigen presentation genes studied. These results demonstrate that tumors can evade preexisting CTLs either by avoiding presentation of the tumor antigen or, surprisingly, by down-regulation of costimulatory molecules. The paradoxical requirements of both antigen and costimulatory molecules at the effector phase raised an interesting question on the nature of antitumor immunity.
Zheng
P
P
Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus 43210, USA.
Sarma
S
S
Guo
Y
Y
Liu
Y
Y
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000502:physiology; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology; D003546:Cysteine Endopeptidases; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes; D009362:Neoplasm Metastasis / Q000276:immunology*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D018122:B7-1 Antigen; D016326:Extracellular Matrix Proteins; D006183:H-2 Antigens; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C489516:Tap2 protein, mouse; D001613:beta 2-Microglobulin; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex