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August 1, 2007 — 根据一项发表于7月30日国家科学研究院会刊的新研究结果，一种抑制身体免疫反应，使得身体无法辨认与摧毁何杰金氏淋巴瘤肿瘤细胞的蛋白质，被证实可能是个新的治疗标的；这项研究也发现，一种称为galectin-1（Gal-1）的碳水化合物结合凝集素，显然可以增强肿瘤血管新生作用，且加强肿瘤细胞运动能力，这两种作用对典型何杰金氏淋巴瘤（cHL）肿瘤来说是非常关键的。
每年在北美有将近20,000个新病患被诊断出罹患cHL，这是一种B细胞恶性肿瘤；cHL的特征是同时具有恶性何杰金氏与Reed-Sternberg细胞，这些是已经被证实过度表现Gal-1的特殊巨大细胞。
主要作者麻州波士顿达那-法柏癌症研究治疗中心淋巴瘤计划主任Margaret Shipp医师表示，我们先前认为这些资料在诊断何杰金氏淋巴瘤上是有用的，因为galectin-1的表现可能是诊断标记的一部份。
但是，她向Medscape表示，就长期的角度来看，最重要的是透过galectin-1我们是否可以改善何杰金氏淋巴瘤的治疗；目前，我们认为抑制galectin-1是值得一试的。
Shipp医师表示，肿瘤细胞会表现并分泌Gal-1，这些接着会与作用型T细胞结合，这对抗肿瘤反应是很重要的；在慢性发炎疾病的实验性研究中，基因重组Gal-1已经被证实可以抑制Th1-依赖型反应、且增加T细胞对诱发性细胞死亡的感受性。
她表示，对抗Gal-1的抗体可能是非常有效的治疗策略。
针对Gal-1的决定是来自于一项广泛性为基础的基因表现资料研究，在这项研究中，Shipp医师与其同事寻找cHL过度表现的基因，相较于广泛性大B细胞淋巴瘤；Shipp医师表示，Galectin-1是何杰金氏瘤中最戏剧性且最一致性过度表现的基因之一；Galectin-1的生化特性与其于何杰金氏症的表现促使我们进行更多的研究。
在这项研究中，研究者使用功能性活体外试验，并且比对cHL与广泛性大B细胞淋巴瘤、以及胸膈大B细胞淋巴瘤细胞株的基因表现；他们发现，Gal-1的表现在cHL细胞中是其他两种形式淋巴瘤的4~29倍。
他们也发现，Reed-Sternberg细胞中的Gal-1降低活化T细胞的存活率，且改变其倾向Th2免疫反应的平衡；Gal-1也显著地增加Th2细胞激素的分泌，包括间白素（IL）-4、-5、-10与-13；综合来看，这两种观察结果强烈地暗示Gal-1于Reed-Stemberg细胞中扮演独特Th2/Treg偏斜的免疫抑制性微观环境角色，就有如于原发性cHL所看到的一样。
Shipp医师指出，大部分治疗都是被设计来杀死肿瘤细胞，且并没有太多研究着墨于肿瘤及周边免疫细胞之间的交互作用。
她表示，基本上，Gal-1的功用就像一个保镖，透过让免疫细胞失去作用，而使得肿瘤细胞对于身体的免疫反应具有抵抗性；这或许是一个例子，操控免疫对肿瘤的反应可能是一项崭新、且可能更加有效的癌症治疗。
Shipp医师与其团队继续进行更多的研究，且着手设计之后可能的临床研究；她表示，为了要能够研发应用于临床试验的产品，我们已经制造出抗体来抑制这个蛋白，我们认为这很具有潜力，且目前已经有足够生物观点的证据指出抑制GA-1在治疗上可能是非常有用的。
这项研究由Miller家庭研究基金会赞助。
Possible New Treatment Target for Hodgkin Lymphoma
By Roxanne Nelson
Medscape Medical News
August 1, 2007 — The identification of a protein that inhibits the body's immune response from recognizing and destroying Hodgkin lymphoma cells might prove to be a new therapeutic target, according to new research that appears in the July 30 online issue of the Proceedings of the National Academy of Sciences. The study also found that the protein, a carbohydrate-binding lectin called galectin-1 (Gal-1), appears to enhance tumor angiogenesis and promote tumor cell motility, 2 processes that are critical for classic Hodgkin lymphoma (cHL) tumors.
Approximately 20,000 new patients are diagnosed in North America and Europe every year with cHL, which is a B cell malignancy. cHL is characterized by small numbers of both malignant Hodgkin and Reed-Sternberg cells, which are distinctive giant cells that have been shown to overexpress Gal-1.
"We already think that these data may be useful in the diagnosis of Hodgkin lymphoma because expression of galectin-1 might be of use as part of a diagnostic signature," said lead investigator Margaret Shipp, MD, director of the Lymphoma Program at the Dana-Farber Cancer Institute in Boston, Massachusetts.
"But what is more important, from a long-term standpoint, is whether we can actually improve the treatment of Hodgkin's lymphoma by going after galectin-1," she told Medscape. "At this point, we think it might be very promising to try to inhibit galectin-1."
Dr. Shipp explained that the tumor cells express and secrete Gal-1, which then binds to the effector T cells that are important to an anti-tumor response. In experimental studies of chronic inflammatory diseases, recombinant Gal-1 has been shown to suppress Th1-dependent responses and to increase T-cell susceptibility to activation-induced cell death.
"There is a possibility that antibodies to Gal-1 might be a very useful treatment approach," she said.
The decision to target Gal-1 came out of a broad-based gene-expression profile study, in which Dr. Shipp and colleagues were looking for genes that were specifically overexpressed in cHL, in comparison to diffuse large B-cell lymphoma. "Galectin-1 was 1 of the genes that was the most dramatically and uniformly overexpressed in Hodgkin lymphoma," said Dr. Shipp. "The combination of the biology of galectin-1 and its expression in Hodgkin's prompted us to do the additional series of studies."
In this study, the researchers used functional in vitro assays and compared the gene expression profiles of cHL with diffuse large B cell lymphoma and mediastinal large B cell lymphoma cell lines. They found that Gal-1 expression was 4 to 29 times more abundant in cHL cells than it was in the other 2 types of lymphoma.
They also found that Gal-1 in Reed-Sternberg cells reduced activated T cell viability and altered the balance toward a Th2 immune response. Gal-1 also greatly increased the secretion of Th2 cytokines, including interleukin (IL)-4, IL-5, IL-10, and IL-13. Combined together, these 2 observations strongly implicate the role that the Gal-1 in Reed-Sternberg cells plays in the development and maintenance of the unique Th2/Treg-skewed immunosuppressive microenvironment seen in primary cHL.
Most treatments are specifically designed to kill the tumor cells, Dr. Shipp pointed out, and there hasn't been that much investigation into attempting to better understand the interaction between the tumor and the surrounding immune cells.
"Basically, Gal-1 is functioning as a bodyguard; it makes the tumor cells resistant to the body's immune system by disabling the immune cells," she said. "This may be an example of a possible lead, where manipulating the immune response to the tumor might be a novel and potentially synergistic way of treating the tumor."
Dr. Shipp and her team are continuing on with this research and thinking ahead to possible clinical trials. "We are already making antibodies in an attempt to inhibit the protein, with the idea of being able to develop a product that can be used in clinical trials," she said. "We think that it is promising enough and there is sufficient evidence from the biology point of view to indicate that inhibiting GA-1 might be very useful in terms of a treatment."
The research was funded by the Miller Family Research Foundation.
Proc Natl Acad Sci U S A. Published online July 30, 2007.