Immunomodulatory effects of interleukin-12 on human tumor-infiltrating lymphocytes.
Interleukin (IL)-12 is a recently described cytokine with multiple immunoregulatory effects on various lymphoid populations, including peripheral blood lymphocytes (PBL), natural killer (NK) cells, and T-cell subsets. We examined the effects of recombinant IL-12 on the immune function of human tumor infiltrating lymphocytes (TIL) from several different tumor types. At an optimal concentration of 50 IU/ml, IL-12 acted as a co-stimulant for TIL recently activated with anti-CD3 antibodies, giving stimulation indices between 2.6 and 9.9. This co-stimulatory effect was independent of IL-2 and was not inhibited by neutralizing antibody to human IL-2. When IL-2 and IL-12 were used synchronously as co-mitogenic stimuli in culture with activated TIL, the effect on proliferation was additive. This additive effect held true over a range of suboptimal concentrations of IL-2 and in different TIL populations. IL-12 did not enhance non-major histocompatibility complex (MHC)-restricted cytotoxicity in the TIL populations tested. TIL cultured with IL-12 killed more autologous tumor targets than TIL maintained in media alone at identical effector/target (E/T) ratios. This effect on cytotoxicity was not as great as that seen in TIL maintained in low-dose IL-2. Co-culture with IL-12 did not change the phenotype of TIL used in these assays. The importance of these findings and possible uses in immunotherapy are discussed.
Andrews
J V
JV
Harvard Medical School, Brigham and Women's Hospital, Department of Surgery, Boston, MA 02115.
Schoof
D D
DD
Bertagnolli
M M
MM
Peoples
G E
GE
Goedegebuure
P S
PS
Eberlein
T J
TJ
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000906:Antibodies / Q000008:administration & dosage; D017252:CD3 Complex; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D007378:Interleukins / Q000008:administration & dosage / Q000494:pharmacology*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000276:immunology
D000276:Adjuvants, Immunologic; D000906:Antibodies; D017252:CD3 Complex; D007376:Interleukin-2; D007378:Interleukins; D011994:Recombinant Proteins; D018664:Interleukin-12