Witalis Mariko, Chang Jinsam, Zhong Ming-Chao, Bouklouch Yasser, Panneton Vincent, Li Joanna, Buch Thorsten, Kim Seok Jin, Kim Won Seog, Ko Young Hyeh, Veillette André, Suh Woong-Kyung
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada.
Molecular Biology Department, University of Montréal, Montréal, QC, Canada.
Blood Adv. 2020 Mar 10;4(5):868-879. doi: 10.1182/bloodadvances.2019001114.
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma driven by a pool of neoplastic cells originating from T follicular helper (Tfh) cells and concomitant expansion of B cells. Conventional chemotherapies for AITL have shown limited efficacy, and as such, there is a need for improved therapeutic options. Because AITL originates from Tfh cells, we hypothesized that AITL tumors continue to rely on essential Tfh components and intimate T-cell-B-cell (T-B) interactions. Using a spontaneous AITL mouse model (Roquinsan/+ mice), we found that acute loss of Bcl6 activity in growing tumors drastically reduced tumor size, demonstrating that AITL-like tumors critically depend on the Tfh lineage-defining transcription factor Bcl6. Because Bcl6 can upregulate expression of signaling lymphocytic activation molecule-associated protein (SAP), which is known to promote T-B conjugation, we next targeted the SAP-encoding Sh2d1a gene. We observed that Sh2d1a deletion from CD4+ T cells in fully developed tumors also led to tumor regression. Further, we provide evidence that tumor progression depends on T-B cross talk facilitated by SAP and high-affinity LFA-1. In our study, AITL-like tumors relied heavily on molecular pathways that support Tfh cell identity and T-B collaboration, revealing potential therapeutic targets for AITL.
血管免疫母细胞性T细胞淋巴瘤（AITL）是一种侵袭性外周T细胞淋巴瘤，由一群源自T滤泡辅助（Tfh）细胞的肿瘤细胞驱动，并伴有B细胞的扩增。AITL的传统化疗疗效有限，因此，需要改进治疗方案。由于AITL起源于Tfh细胞，我们推测AITL肿瘤继续依赖于关键的Tfh成分以及紧密的T细胞 - B细胞（T - B）相互作用。使用自发性AITL小鼠模型（Roquinsan/+小鼠），我们发现正在生长的肿瘤中Bcl6活性的急性丧失显著减小了肿瘤大小，表明类似AITL的肿瘤严重依赖于Tfh谱系定义转录因子Bcl6。因为Bcl6可以上调信号淋巴细胞激活分子相关蛋白（SAP）的表达，已知该蛋白可促进T - B结合，我们接下来靶向编码SAP的Sh2d1a基因。我们观察到在完全发育的肿瘤中从CD4 + T细胞中删除Sh2d1a也导致肿瘤消退。此外，我们提供证据表明肿瘤进展依赖于由SAP和高亲和力LFA - 1促进的T - B相互作用。在我们的研究中，类似AITL的肿瘤严重依赖于支持Tfh细胞特性和T - B协作的分子途径，揭示了AITL的潜在治疗靶点。
