Regulatory effects of interleukin-4 on tumor-infiltrating lymphocytes derived from human renal cell carcinoma.
We have studied the effects of interleukin-4 (IL-4) on the expansion, proliferation, phenotype, and antitumor activity of tumor-infiltrating lymphocytes (TIL) derived from human renal cell carcinoma. Cultures were obtained from three primary renal tumors and one group of tumor-invaded, regional lymph nodes. IL-4 induced a significant increase in lymphocyte expansion and proliferation, but the response was dependent on the concurrent dose of IL-2 in culture. Increased growth activity was only observed in those cultures receiving low doses (20 U/ml) of IL-2 (average increase of fold expansion of 6.5, P < 0.01) with no changes in growth activity in the high dose (1000 U/ml) cultures. The combination of low dose IL-2 and IL-4 (200 U/ml) promoted lymphocyte growth significantly better than high dose IL-2 alone, the current standard growth regimen for in vitro expansion of TIL. TIL grown in the presence of IL-4 significantly reduced the level of non-specific, non-major histocompatibility complex-restricted antitumor activity (P < 0.01 for allogeneic renal, nonrenal, and NK-sensitive K562 cells), while exhibiting no effect on the level of autologous killing. This is in contrast to previous findings of significant enhancement of autologous antitumor activity using IL-4 on tumor-specific, melanoma-derived TIL. We also evaluated the effects of irradiated autologous tumor stimulation (TIL:tumor ratio, 10:1) on TIL cultures. Addition of autologous tumor cells increased expansion and proliferation of all cultures regardless of concurrent lymphokines present in the culture media (average increase fold expansion of 2.21, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Peyret
C
C
Department of Surgery, University of California, Los Angeles School of Medicine.
Bochner
B H
BH
Lee
T Y
TY
Koo
A S
AS
deKernion
J B
JB
Belldegrun
A
A
D002292:Carcinoma, Renal Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000502:physiology; D010641:Phenotype; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D015847:Interleukin-4