T-cells infiltrating renal cell carcinoma display a poor proliferative response even though they can produce interleukin 2 and express interleukin 2 receptors.
The fact that progressing tumors contain a significant infiltrate of T-cells brings into question the competency of the infiltrating T-lymphocytes (T-TIL). We have examined the role of the T-cell receptor/CD3 complex and/or the interleukin 2 receptor (IL2R) in responsiveness of T-cells that infiltrate human renal cell carcinoma. T-TIL display a poor proliferative response to interleukin 2 (IL2) alone, IL2 in combination with antibody to CD3, or mitogen stimulation. The proliferative unresponsiveness was not related to low expression of CD3 or IL2R beta as the percentage of T-cells expressing CD3 and IL2R beta were comparable in both T-TIL and peripheral blood T-cells obtained from the same patient. In contrast to the lack of proliferative activity, stimulation of T-TIL or peripheral blood lymphocytes with phytohemagglutinin or anti-CD3 resulted in comparable levels of both IL2 and gamma-interferon mRNA and protein expression. While levels of IL2R alpha were low in unstimulated T-TIL and peripheral blood lymphocytes, anti-CD3 antibody or IL2 were capable of inducing surface expression of this protein in both cell populations. IL2R alpha mRNA levels were comparable in T-cells from the tumor and peripheral blood although in some experiments both the percentage of IL2R alpha-positive cells and the density of surface expression per cell were reduced in T-TIL. This reduced IL2R alpha expression on T-TIL was not responsible for the proliferative unresponsiveness since T-TIL that expressed both IL2R alpha and/or IL2R beta still failed to respond to high doses of IL2. Thus T-TIL display a selective loss of response to at least two well defined extracellular stimuli. While T-TIL exhibit a poor proliferative response regardless of the form of stimulation these cells remain sensitive to both anti-CD3 and IL2 in terms of IL2 and gamma-interferon or IL2R alpha expression, respectively. The fact that proliferative unresponsiveness exists even though T-TIL can produce IL2 and express IL2R alpha/beta suggests that T-TIL have a selective loss of a common intracellular signaling pathway which is requisite to proliferation but not other aspects of response to antigenic stimulation.
Alexander
J P
JP
Department of Urology, Cleveland Clinic Foundation, Ohio 44195.
Kudoh
S
S
Melsop
K A
KA
Hamilton
T A
TA
Edinger
M G
MG
Tubbs
R R
RR
Sica
D
D
Tuason
L
L
Klein
E
E
Bukowski
R M
RM
D000328:Adult; D000368:Aged; D001483:Base Sequence; D017252:CD3 Complex / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D017252:CD3 Complex; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma