Monocyte-dependent, serum-borne suppressor of induction of lymphokine-activated killer cells in lymphocytes from melanoma patients.
Both phytohemagglutinin-induced cytotoxicity and recombinant-interleukin-2 (rIL-2)-induced lymphokine-activated killer (LAK) activity against noncultured melanoma cells were significantly reduced when peripheral blood mononuclear cells (PBMC) from patients with metastatic melanoma were incubated in RPMI medium 1640 and 10% autologous human serum instead of 10% fetal calf serum, while serum from either healthy donors or patients with primary melanoma did not affect the level of cytotoxicity. The serum-mediated suppression was not restricted by major histocompatibility complex and was time-dependent. Addition of 10% human serum from the patients with metastatic melanoma [HS-Pt(m)] to the culture of PBMC with rIL-2 at the same time or 1 day after incubation significantly inhibited LAK activity. However, addition of 10% HS-Pt(m) 2 or 3 days after incubation did not inhibit LAK activity. Incubation of PBMC for 2 h with a high dose (10(4) U/ml) of rIL-2 in the presence of 10% HS-Pt(m), followed by incubation in the absence of either rIL-2 or HS-Pt(m), did not affect LAK cell activity. These results suggest that HS-Pt(m) inhibits the early stage of LAK cell differentiation, rather than the binding of rIL-2 to PBMC or a later stage in the differentiation. In contrast to PBMC, monocyte-depleted peripheral blood lymphocytes exhibited comparable levels of LAK activity when cultured with rIL-2 either in 10% fetal calf serum, 10% human serum from healthy donors or 10% HS-Pt(m). Addition of purified autologous monocytes to the culture of monocyte-depleted peripheral blood lymphocytes with rIL-2 suppressed LAK cell induction when 10% HS-Pt(m) was present. Thus serum-mediated suppression of LAK cell induction is largely dependent on the presence of monocytes, which may produce a secondary inhibitor that acts on lymphocytes. Addition of indomethacin to the culture did not reverse this monocyte-dependent serum-mediated suppression in a majority of cases, suggesting that prostaglandin E2 does not have a major role in the suppression.
Itoh
K
K
Division of Surgery, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Pellis
N R
NR
Balch
C M
CM
D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008545:Melanoma / Q000097:blood* / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D009363:Neoplasm Proteins; D010835:Phytohemagglutinins; D011994:Recombinant Proteins / Q000494:pharmacology
D006023:Glycoproteins; D007376:Interleukin-2; D009363:Neoplasm Proteins; D010835:Phytohemagglutinins; D011994:Recombinant Proteins; C038588:serum immunosuppressive factor, human; D007213:Indomethacin