Rengstl Benjamin, Schmid Frederike, Weiser Christian, Döring Claudia, Heinrich Tim, Warner Kathrin, Becker Petra S A, Wistinghausen Robin, Kameh-Var Sima, Werling Eva, Billmeier Arne, Seidl Christian, Hartmann Sylvia, Abken Hinrich, Küppers Ralf, Hansmann Martin-Leo, Newrzela Sebastian
Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School , Frankfurt am Main, Germany.
Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School, Frankfurt am Main, Germany; Center for Molecular Medicine Cologne, University of Cologne, and Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
Oncoimmunology. 2016 Mar 16;5(6):e1160186. doi: 10.1080/2162402X.2016.1160186. eCollection 2016 Jun.
Hodgkin lymphoma (HL) presents with a unique histologic pattern. Pathognomonic Hodgkin and Reed-Sternberg (HRS) cells usually account for less than 1% of the tumor and are embedded in a reactive infiltrate mainly comprised of CD4(+) T cells. HRS cells induce an immunosuppressive microenvironment and thereby escape antitumor immunity. To investigate the impact of interactions between HRS cells and T cells, we performed long-term co-culture studies that were further translated into a xenograft model. Surprisingly, we revealed a strong antitumor potential of allogeneic CD4(+) T cells against HL cell lines. HRS and CD4(+) T cells interact by adhesion complexes similar to immunological synapses. Tumor-cell killing was likely based on the recognition of allogeneic major histocompatibility complex class II (MHC-II) receptor, while CD4(+) T cells from MHC-II compatible donors did not develop any antitumor potential in case of HL cell line L428. However, gene expression profiling (GEP) of co-cultured HRS cells as well as tumor infiltration of matched CD4(+) T cells indicated cellular interactions. Moreover, matched CD4(+) T cells could be activated to kill CD30(+) HRS cells when redirected with a CD30-specific chimeric antigen receptor. Our work gives novel insights into the crosstalk between HRS and CD4(+) T cells, suggesting the latter as potent effector cells in the adoptive cell therapy of HL.
霍奇金淋巴瘤（HL）呈现出独特的组织学模式。具有诊断意义的霍奇金和里德-斯腾伯格（HRS）细胞通常占肿瘤的比例不到1%，并嵌入主要由CD4(+) T细胞组成的反应性浸润中。HRS细胞诱导免疫抑制微环境，从而逃避抗肿瘤免疫。为了研究HRS细胞与T细胞之间相互作用的影响，我们进行了长期共培养研究，并进一步转化为异种移植模型。令人惊讶的是，我们发现同种异体CD4(+) T细胞对HL细胞系具有强大的抗肿瘤潜力。HRS细胞和CD4(+) T细胞通过类似于免疫突触的黏附复合物相互作用。肿瘤细胞杀伤可能基于对同种异体主要组织相容性复合体II类（MHC-II）受体的识别，而来自MHC-II相容供体的CD4(+) T细胞在HL细胞系L428的情况下没有产生任何抗肿瘤潜力。然而，共培养的HRS细胞的基因表达谱（GEP）以及匹配的CD4(+) T细胞的肿瘤浸润表明存在细胞间相互作用。此外，当用CD30特异性嵌合抗原受体进行重定向时，匹配的CD4(+) T细胞可以被激活以杀死CD30(+) HRS细胞。我们的工作为HRS细胞与CD4(+) T细胞之间的相互作用提供了新的见解，表明后者在HL的过继性细胞治疗中是有效的效应细胞。
