Kottke Timothy, Pulido Jose, Thompson Jill, Sanchez-Perez Luis, Chong Heung, Calderwood Stuart K, Selby Peter, Harrington Kevin, Strome Scott E, Melcher Alan, Vile Richard G
Departments of Molecular Medicine, Ophthalmology and Ocular Oncology, and Immunology, Mayo Clinic, Rochester, Minnesota, USA.
Cancer Res. 2009 Oct 1;69(19):7767-74. doi: 10.1158/0008-5472.CAN-09-1597. Epub 2009 Sep 8.
We have a long-term interest in the connectivity between autoimmunity and tumor rejection. However, outside of the melanocyte/melanoma paradigm, little is known about whether autoimmune responses to normal tissue can induce rejection of tumors of the same histologic type. Here, we induced direct, pathogen-like cytotoxicity to the normal pancreas in association with the immune adjuvant heat shock protein 70. In sharp contrast to our studies with a similar approach for the treatment of prostate cancer, inflammatory killing of the normal pancreas induced a Th1-like, anti-self-response to pancreatic antigens, which was rapidly suppressed by a concomitant suppressive regulatory T cell (Treg) response. Interestingly, even when Treg cells were depleted, the Th1-like response was insufficient to induce significant ongoing autoimmunity. However, the Th1-like response to antigens expressed in the pancreas at the time of damage was sufficient to induce rejection of tumors expressing either a foreign (ova) antigen or fully syngeneic tumor antigens (on Panc02 tumor cells), provided that Treg were depleted before inflammatory killing of the normal pancreas. Taken together, these data indicate that profound differences exist between the immunoprotective mechanisms in place between different tissues (pancreas and prostate) in their response to pathogen-like damage. Moreover, they also show that, although multiple layers of immunologic safeguards are in place to prevent the development of severe autoimmune consequences in the pancreas (in contrast to the prostate), tumor rejection responses can still be decoupled from pathologic autoimmune responses in vivo, which may provide novel insights into the immunotherapeutic treatment of pancreatic cancer.
我们长期关注自身免疫与肿瘤排斥之间的联系。然而，除了黑素细胞/黑色素瘤范例之外，对于针对正常组织的自身免疫反应是否能诱导相同组织学类型肿瘤的排斥反应，人们知之甚少。在此，我们利用免疫佐剂热休克蛋白70诱导对正常胰腺产生直接的、类似病原体的细胞毒性。与我们用类似方法治疗前列腺癌的研究形成鲜明对比的是，对正常胰腺的炎性杀伤诱导了针对胰腺抗原的Th1样抗自身反应，该反应迅速被伴随的抑制性调节性T细胞（Treg）反应所抑制。有趣的是，即使Treg细胞被耗尽，Th1样反应也不足以诱导显著的持续性自身免疫。然而，在损伤时对胰腺中表达的抗原的Th1样反应足以诱导表达外来（卵清蛋白）抗原或完全同基因肿瘤抗原（在Panc02肿瘤细胞上）的肿瘤的排斥，前提是在对正常胰腺进行炎性杀伤之前耗尽Treg。综上所述，这些数据表明不同组织（胰腺和前列腺）对类似病原体损伤的免疫保护机制存在深刻差异。此外，它们还表明，尽管有多层免疫保障措施来防止胰腺（与前列腺不同）发生严重的自身免疫后果，但肿瘤排斥反应在体内仍可与病理性自身免疫反应解耦，这可能为胰腺癌的免疫治疗提供新的见解。
