Suppressed T-cell receptor zeta chain expression and cytokine production in pancreatic cancer patients.
Suppression of various functions of T cells derived from cancer patients has been linked previously to changes in the T-cell receptor (TCR)-associated signal transduction molecules, in particular the zeta chain of the TCR complex. In this study, we have examined the TCRzeta chain expression and cytokine production in vivo and in vitro in T cells of patients with metastatic adenocarcinomas of the pancreas that participated in a Phase I clinical trial of the MUC1 peptide plus bacillus Calmette-Guerin cancer vaccine. A majority of the patients had reduced TCRzeta chain expression and interleukin 4 production by T cells, and all of the patients showed decreased production of IFN-gamma of their peripheral T cells when compared with healthy individuals. Peripheral blood T cells were activated with the phorbol ester phorbol myrisate acetate and ionomycin to show that although aberrant TCRzeta chain expression and decreased cytokine production were often correlated, the reduced cytokine production was not simply a consequence of an impaired TCRzeta chain expression. Rather, these are two separate but parallel defects in signal transduction in T cells, which are potentially modulated by the same mechanisms. Half of the patients showed an improvement for TCRzeta chain or IFN-gamma expression after vaccination.
Schmielau
J
J
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Nalesnik
M A
MA
Finn
O J
OJ
D000230:Adenocarcinoma / Q000378:metabolism; D001706:Biopsy; D016207:Cytokines / Q000096:biosynthesis*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis*; D018396:Mucin-1 / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D008565:Membrane Proteins; D018396:Mucin-1; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D015847:Interleukin-4; D007371:Interferon-gamma