Schoof D D, Terashima Y, Peoples G E, Goedegebuure P S, Andrews J V, Richie J P, Eberlein T J
Brigham & Women's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115.
Cell Immunol. 1993 Aug;150(1):114-23. doi: 10.1006/cimm.1993.1183.
The underlying cause for the observed poor antitumor activity of lymphocytes resident, in situ, in freshly resected human renal cell carcinoma (RCC) is unknown. To examine the basis for this observation we evaluated 217 T cell clones established from 20 consecutive patients with renal cell carcinoma. Of these, 75% were CD4+, 22% were CD8+, and 3% were NK+. Cytotoxic T cell function of CD4+ and CD8+ T cell clones was assessed by antibody-induced triggering of the TcR/CD3 complex. Nearly 93% of the CD4+ clones possessed poor cytolytic activity defined as < 50% killing (E:T, 50:1). Alternatively, nearly 80% of CD8+ clones possessed strong cytolytic activity defined as > or = 50% killing. In all T cell clones tested, MHC nonrestricted killing against Daudi or K562 was not observed. Overall, 77% of the T cell clones isolated from patients with RCC in this study were characterized by poor antitumor cytotoxic function; only 22% of the clones displayed strong cytolytic activity. Clones with strong cytotoxic function were tested for cytotoxic function against autologous tumor. However, all clones tested demonstrated little to no tumoricidal activity against autologous tumor. These results indicate that cytolytic T cells, while present in RCC, are not effectively activated by tumor to express CTL function. The immunobiology of CD4+ T cell clones was further evaluated. Thirty-two CD4+ clones from seven patients revealed distinct patterns of cytokine production following TcR/CD3 activation. CD4+ clones could be divided into IL-2 nonproducers and IL-2 producers. A total of 27/32 clones did not produce IL-2 following activation and IFN-gamma production by IL-2 nonproducers was more than threefold less than that by IL-2 producers. However, no differences were found in the levels of IL-4, IL-6, GM-CSF, or TNF-alpha between the two groups. Antitumor cytotoxicity mediated by CD4+ clones did not correlated with cytokine production. These results demonstrate that among T cells resident in human RCC, the predominant type of lymphocyte population consists of noncytolytic helper CD4+ T cells capable of secreting IL-4, but importantly not IL-2, and low levels of IFN-gamma following activation, thus resembling murine Th2 cells. Only a minor contribution by Th0-like cells was observed (i.e., CD4+ clones capable of secreting IL-2, IL-4, and IFN-gamma following activation).(ABSTRACT TRUNCATED AT 400 WORDS)
目前尚不清楚原位存在于新鲜切除的人类肾细胞癌（RCC）中的淋巴细胞抗肿瘤活性较差的潜在原因。为了探究这一观察结果的依据，我们评估了从20例连续的肾细胞癌患者中建立的217个T细胞克隆。其中，75%为CD4 +，22%为CD8 +，3%为NK +。通过抗体诱导的TcR/CD3复合物触发来评估CD4 +和CD8 + T细胞克隆的细胞毒性T细胞功能。近93%的CD4 +克隆具有较差的细胞溶解活性，定义为杀伤率<50%（效靶比，50:1）。相比之下，近80%的CD8 +克隆具有较强的细胞溶解活性，定义为杀伤率≥50%。在所有测试的T细胞克隆中，未观察到针对Daudi或K562的MHC非限制性杀伤。总体而言，本研究中从RCC患者分离的T细胞克隆中，77%的特征是抗肿瘤细胞毒性功能较差；只有22%的克隆表现出较强的细胞溶解活性。对具有强细胞毒性功能的克隆进行了针对自体肿瘤的细胞毒性功能测试。然而，所有测试的克隆对自体肿瘤几乎没有或没有杀瘤活性。这些结果表明，虽然细胞溶解T细胞存在于RCC中，但它们未被肿瘤有效激活以表达CTL功能。对CD4 + T细胞克隆的免疫生物学进行了进一步评估。来自7例患者的32个CD4 +克隆在TcR/CD3激活后显示出不同的细胞因子产生模式。CD4 +克隆可分为IL - 2非产生者和IL - 2产生者。共有27/32个克隆在激活后不产生IL - 2，IL - 2非产生者产生的IFN - γ比IL - 2产生者少三倍以上。然而，两组之间在IL - 4、IL - 6、GM - CSF或TNF - α水平上未发现差异。CD4 +克隆介导的抗肿瘤细胞毒性与细胞因子产生无关。这些结果表明，在人类RCC中存在的T细胞中，主要的淋巴细胞群体由非细胞溶解的辅助性CD4 + T细胞组成，这些细胞能够分泌IL - 4，但重要的是不分泌IL - 2，激活后产生低水平的IFN - γ，因此类似于小鼠Th2细胞。仅观察到少量类似Th0样细胞的贡献（即激活后能够分泌IL - 2、IL - 4和IFN - γ的CD4 +克隆）。（摘要截短于400字）
