Expression of TNF-related apoptosis-inducing ligand (TRAIL) and its receptors in gastric carcinoma and tumor-infiltrating lymphocytes: a possible mechanism of immune evasion of the tumor.
OBJECTIVE
TNF-related apoptosis-inducing ligand (TRAIL) and its receptors have recently been known to be responsible for apoptotic signaling molecules in tumor cell lines and tissues. These molecules have been reported to be expressed on merely a transcription level, but not on a protein level. Moreover, little is known about TRAIL-mediated apoptosis in human carcinoma in vivo.


METHODS
We investigated the presence and functional status of TRAIL and its receptors, DR4, DR5, and DcR2 on tumor as well as tumor-infiltrating lymphocytes (TIL) in primary ( n=37), and metastatic gastric carcinoma from malignant ascites ( n=37) by a flow cytometry. In addition, phenotypic proportions of major T-cell subsets or B-cells in TIL were also determined.


RESULTS
Membrane-bound TRAIL/its receptors are constitutively expressed at high levels in primary and metastatic carcinomas in nearly all the patients. Apoptotic tumor cells detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) were barely identified in primary and metastatic carcinomas. TIL in primary carcinoma showed a very low level of expression of TRAIL/its receptors and TUNEL-positive cells. In metastatic carcinoma, however, there was significant overexpression of TRAIL/its receptors in TIL associated with a higher frequency of apoptotic cell death detected by TUNEL. The TIL within metastatic carcinoma, but not within primary carcinoma, revealed the increased proportions of CD3(+) T cells bearing CD8(+)CD11b(-), CD8(+)CD11b(+), and CD4(+)CD62L(-), CD4(+)CD62L(+) surface phenotype in patients.


CONCLUSIONS
These results suggest that TRAIL(+) and DcR2(+) metastatic carcinoma from malignant ascites could not only have resistance to DR4/DR5-induced apoptosis, but also might take the TRAIL-mediated counterattack against activated CD3(+) T cells. These functions of the cancer cells would neutralize host immune responses at the effector phase, and accelerate further invasion and/or metastasis of carcinoma through the escape from immune attack.
Koyama
Shohei
S
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-City, Ibaraki 305-8575, Japan. s-koyama@md.tsukuba.ac.jp
Koike
Naoto
N
Adachi
Shinya
S
D000328:Adult; D000368:Aged; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000032:analysis*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001201:Ascites / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D001665:Binding Sites; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008565:Membrane Proteins; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D010641:Phenotype; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D015703:Antigens, CD; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C451501:TNFRSF10D protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha