Alexander J P, Kudoh S, Melsop K A, Hamilton T A, Edinger M G, Tubbs R R, Sica D, Tuason L, Klein E, Bukowski R M
Department of Urology, Cleveland Clinic Foundation, Ohio 44195.
Cancer Res. 1993 Mar 15;53(6):1380-7.
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.
进展期肿瘤中存在大量T细胞浸润这一事实，让人质疑浸润性T淋巴细胞（T-TIL）的功能。我们研究了T细胞受体/CD3复合物和/或白细胞介素2受体（IL2R）在浸润人肾细胞癌的T细胞反应性中的作用。T-TIL对单独的白细胞介素2（IL2）、IL2与抗CD3抗体联合使用或丝裂原刺激的增殖反应较差。增殖无反应性与CD3或IL2Rβ的低表达无关，因为在T-TIL和从同一患者获得的外周血T细胞中，表达CD3和IL2Rβ的T细胞百分比相当。与缺乏增殖活性相反，用植物血凝素或抗CD3刺激T-TIL或外周血淋巴细胞，导致IL2和γ干扰素mRNA及蛋白表达水平相当。虽然未刺激的T-TIL和外周血淋巴细胞中IL2Rα水平较低，但抗CD3抗体或IL2能够在这两种细胞群体中诱导该蛋白的表面表达。肿瘤和外周血T细胞中的IL2RαmRNA水平相当，尽管在一些实验中，T-TIL中IL2Rα阳性细胞的百分比和每个细胞表面表达的密度均降低。T-TIL上这种降低的IL2Rα表达并非增殖无反应性的原因，因为同时表达IL2Rα和/或IL2Rβ的T-TIL对高剂量IL2仍无反应。因此，T-TIL对至少两种明确的细胞外刺激表现出选择性反应丧失。虽然无论刺激形式如何，T-TIL的增殖反应都较差，但这些细胞在IL2和γ干扰素表达方面分别对抗CD3和IL2仍敏感。即使T-TIL能够产生IL2并表达IL2Rα/β，但仍存在增殖无反应性，这一事实表明T-TIL选择性丧失了一种共同的细胞内信号通路，该通路是增殖所必需的，但对抗抗原刺激的其他方面并非必需。
