Proliferative and cytolytic potentials of purified human tumor-infiltrating T lymphocytes. Impaired response to mitogen-driven stimulation despite T-cell receptor expression.
Using limiting dilution analysis (LDA) we have previously shown that in most instances, the frequency (F) of proliferative T lymphocyte precursors (PTL-P) was strikingly reduced in tumor-infiltrating lymphocytes (TIL). In this study involving 19 cases, we show that the impaired clonogenic potential of CD2+ TILs is primarily caused by an intrinsic defect rather than to suppressor T cells or to a direct effect of the tumor cells usually present in the culture system. This was demonstrated by experiments in which the F of PTL-Ps was quantitated both in highly purified CD2+ TILs (using a cell-sorter) and in non-purified TIL suspensions (still containing tumor cells), which originated from the same biopsy specimen. The F of PTL-Ps was virtually identical in either sorted or nonsorted suspensions and the data from LDA were always consistent with the single-hit Poisson model, indicating that no suppressor cells interfered with growth of CD2+ TIL. Stimulation of sorted CD2+ TIL in low-density cultures by either phytohemagglutinin or anti-CD3-monoclonal antibody (MAb) indicated that the antigen-dependent activation pathway was impaired, although structurally intact T-cell receptor (TCR) complexes were apparently expressed, as assessed by immunofluorescence. The depressed proliferative response of CD2+ TIL could not be reversed in vitro when phorbol-esters were used in combination with ionomycin, which bypass the TCR. Nevertheless, 180 clones obtained from 8 cases were analyzed for their cytolytic activity. The majority mediated specific lytic activity (against unknown antigens), as assessed by lectin-dependent cell cytotoxicity, whereas only 6% of them manifested lymphokine-activated killing on appropriate targets.
Miescher
S
S
Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland.
Stoeck
M
M
Qiao
L
L
Barras
C
C
Barrelet
L
L
von Fliedner
V
V
D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis*; D017252:CD3 Complex; D002455:Cell Division; D002469:Cell Separation; D002470:Cell Survival; D004987:Ethers / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000032:analysis; D015759:Ionomycin; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000032:analysis*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D004987:Ethers; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate