Fisk B, Hudson J M, Kavanagh J, Wharton J T, Murray J L, Ioannides C G, Kudelka A P
Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Anticancer Res. 1997 Jan-Feb;17(1A):45-53.
Identifying target antigens for tumor-reactive T cells is important for understanding the mechanisms of tumor escape and developing novel anticancer therapies. To date, mainly CTL responses from tumor infiltrating associated lymphocytes (TIL/TAL) to peptide antigens have been investigated in ovarian cancer. In the present study, the ability of self-peptides derived from HER-2/neu proto-oncogene product (HER-2) to stimulate proliferation of PBMC from healthy donors and ovarian cancer patients has been assessed. Peptide sequences from HER-2 containing anchors for major human MHC-class II molecules have been identified. These peptides induced proliferative and cytokine responses at higher frequency in healthy donors than ovarian cancer patients. Four HER-2 peptides corresponding to positions: 396-406, 474-487, 777-789, and 884-899 were able to stimulate proliferation of a larger number of healthy donors than three other distinct HER-2 peptides 449-464, 975-987 and 1086-1098. The pattern of responses of twenty five ovarian cancer patients was different from that in healthy donors. T cell lines were developed by stimulation with peptides from PBMC of an ovarian cancer patient who showed a stable response to all four HER-2 peptides for over six months. Each T cell line was different in its ability to secrete IFN-gamma and IL-10. These results demonstrate (a) that self-peptides from HER-2 can stimulate expansion of T cells in both healthy donors and ovarian cancer patients, and (b) the ability of different peptides to stimulate secretion of different cytokines from lymphocytes of ovarian cancer patients. These results may be important for understanding the mechanisms of tolerance and autoimmunity in human cancers.
识别肿瘤反应性T细胞的靶抗原对于理解肿瘤逃逸机制和开发新型抗癌疗法至关重要。迄今为止，在卵巢癌中主要研究了肿瘤浸润相关淋巴细胞（TIL/TAL）对肽抗原的CTL反应。在本研究中，评估了源自HER-2/neu原癌基因产物（HER-2）的自身肽刺激健康供体和卵巢癌患者外周血单核细胞（PBMC）增殖的能力。已鉴定出HER-2中包含主要人类MHC-II类分子锚定残基的肽序列。与卵巢癌患者相比，这些肽在健康供体中诱导增殖和细胞因子反应的频率更高。与其他三种不同的HER-2肽449-464、975-987和1086-1098相比，对应于396-406、474-487、777-789和884-899位的四种HER-2肽能够刺激更多健康供体的PBMC增殖。25名卵巢癌患者的反应模式与健康供体不同。通过用一名对所有四种HER-2肽均表现出超过六个月稳定反应的卵巢癌患者的PBMC中的肽进行刺激，建立了T细胞系。每个T细胞系分泌IFN-γ和IL-10的能力各不相同。这些结果表明：（a）HER-2的自身肽能够刺激健康供体和卵巢癌患者的T细胞扩增；（b）不同肽刺激卵巢癌患者淋巴细胞分泌不同细胞因子的能力。这些结果对于理解人类癌症中的耐受和自身免疫机制可能具有重要意义。
